ASCP 2012

PHOENIX – Interest in the use of intranasal oxytocin for the treatment of psychiatric disorders has expanded in recent years, and several new studies suggest that it may have benefit in patients with schizophrenia.

The neuropeptide, which is associated with a wide variety of social behaviors in diverse species, may be particularly suited for treating schizophrenia, Deanna Kelly, Pharm.D., said during a symposium at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

"Schizophrenia is a disorder that is associated with a spectrum of social and emotional deficits, such as impaired perception of emotions, impaired social cue perception, and biased reasoning about certain types of social information. It is also a thought disorder associated with anxiety and mistrust," said Dr. Kelly of the University of Maryland, Baltimore.

It is well established that oxytocin regulates many of these factors, and compelling evidence suggests the oxytocin system is dysregulated in patients with schizophrenia.

Emerging clinical data demonstrate that oxytocin administrated via the intranasal route, which is believed to provide a favorable pathway for the peptide into the central nervous system, provides benefit with respect to emotion recognition, positive and negative core symptoms, social cognitive measures, and neurocognition.

In one double-blind, placebo-controlled, crossover study, oxytocin was shown to improve emotion recognition, Bruno Averbeck, Ph.D., reported. In an initial experiment, 30 stable, medicated community-dwelling patients with schizophrenia and 29 control subjects matched for age and IQ completed an emotion discrimination task involving images of facial expressions representing specific emotions. Some images included a single emotion, and others were morphed images, depicting two commonly confused emotions such as surprise and fear.

Patients with schizophrenia were less able than controls to accurately recognize emotions using both unmorphed and morphed images, although both groups performed worse on identifying morphed emotions, said Dr. Averbeck of the National Institute of Mental Health.

In the crossover study, the effects of one 24-IU dose of oxytocin on the same emotion recognition task were measured in 21 patients with schizophrenia. Compared with performance without oxytocin, there was a 25% improvement in emotion recognition following oxytocin treatment, with improved recognition of certain emotions, such as happiness and sadness, but not others, such as surprise, he said (Psychol. Med. 2012;42:259-66).

A possible explanation for the improved performance on emotion recognition tasks following intranasal oxytocin administration is increased saccades to the eye region. A great deal of emotion is expressed through the eyes, and patients with schizophrenia are prone to avoidance of the eye region, Dr. Averbeck explained, noting that prior studies in patients with autism have shown that oxytocin increases saccades and emotion recognition.

In two other proof-of-concept trials, intranasal oxytocin was found to significantly reduce both positive and negative schizophrenia symptoms, and to improve social dysfunction.

A team of researchers at the University of California, San Diego (UCSD), conducted one of the studies – a randomized, placebo-controlled crossover trial of 15 adult patients with residual symptoms despite therapy. In the trial, either placebo or intranasal oxytocin, taken daily for 3 weeks and titrated to 40 IU (5 sprays) twice daily, was given in addition to stable doses of antipsychotic medication. The order of placebo and oxytocin was randomly assigned with a 1-week washout between treatments (Biol. Psychiatry 2010;68:678-80).

Oxytocin treatment for 3 weeks significantly reduced scores on the Positive and Negative Symptoms Scale (PANSS), with a difference of 5.46 points between groups on total scores. Clinical Global Impression-Improvement Scale (CGI-I) scores also were significantly improved in the treatment group, compared with placebo after 3 weeks of treatment, said Dr. David Feifel of UCSD, who led the study.

The findings support those of prior studies that also have demonstrated antipsychotic effects of oxytocin, and which have suggested oxytocin’s ability to ameliorate the symptoms of schizophrenia, he said.

In a separate proof-of-concept study, a team of researchers at the University of North Carolina, Chapel Hill (UNC), also found that after controlling for baseline measures, oxytocin treatment was associated with significantly greater declines in PANSS total scores, compared with placebo (least squares mean differences of 70.56 vs. 77.21), and with trends toward significantly greater declines vs. placebo in PANSS general subscale scores (least squares mean differences of 34.34 vs. 38.26).

In that 14-day parallel-arm study, led by Dr. Cort A. Pedersen of UNC, 14 adult patients were treated with 24 IU of intranasal oxytocin twice daily in addition to their stable regimens of antipsychotic medication, and 11 received placebo.

In both of these proof-of-concept studies, intranasal oxytocin was well tolerated, and also produced improvement on highly relevant secondary measures.

For example, in the UCSD study, oxytocin treatment was associated with significant improvement, compared with placebo, on California Verbal Learning Test scores on total recall, short-delay free recall, short-delay cued recall, total repetitions, and total recall discriminability.

In the UNC study, oxytocin treatment was associated with significant improvement in accurate identification of third-order false belief in the Brüne Theory of Mind Test (an evaluation of the ability to understand others’ thoughts and feelings). There also was a trend toward more accurate identification of second-order false belief and deception, and in the ability to rate faces as less untrustworthy. "None of these measures changed significantly in the placebo group," Dr. Pedersen said.

The improvements in social functioning are of note, because this is an aspect of schizophrenia that is a major cause of disability, and which tends to respond poorly to antipsychotic medications, according to Dr. Pedersen. The improvement seen with respect to neurocognition might further improve social and general functioning in patients with schizophrenia, he added.

Not all recent studies of oxytocin in schizophrenia have resulted in positive findings. In fact, a third proof-of-concept study by Dr. Kelly and her colleague, Dr. Mary Lee of the National Institute on Drug Abuse, did not demonstrate significant differences between oxytocin and placebo on many of the measures used in the two positive proof-of-concept studies. Thus, it remains unclear whether higher doses and longer duration of treatment would improve outcomes.

"The exciting thing is that these questions will hopefully be answered in several ongoing trials with higher doses," Dr. Feifel said, noting that one trial currently underway is evaluating doses ranging from 40 IU to 160 IU given for longer durations.

Dr. Pederson noted that he "won’t be surprised at all if [treatment with oxytocin] augments nonpharmacologic interventions such as social, cognitive, and neurocognitive training."

"Also, it may be more effective if treatment starts early in the course of disease rather than after a patient has been sick for decades," he said.

Dr. Kelly disclosed a financial relationship with Bristol-Myers Squibb. Dr. Pedersen disclosed holding a U.S. Provisional Patent Application, and receiving research support from the Foundation of Hope for Research and Treatment of Mental Illness and from the Stanley Medical Research Institute.

PHOENIX – Interest in the use of intranasal oxytocin for the treatment of psychiatric disorders has expanded in recent years, and several new studies suggest that it may have benefit in patients with schizophrenia.

The neuropeptide, which is associated with a wide variety of social behaviors in diverse species, may be particularly suited for treating schizophrenia, Deanna Kelly, Pharm.D., said during a symposium at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

"Schizophrenia is a disorder that is associated with a spectrum of social and emotional deficits, such as impaired perception of emotions, impaired social cue perception, and biased reasoning about certain types of social information. It is also a thought disorder associated with anxiety and mistrust," said Dr. Kelly of the University of Maryland, Baltimore.

It is well established that oxytocin regulates many of these factors, and compelling evidence suggests the oxytocin system is dysregulated in patients with schizophrenia.

Emerging clinical data demonstrate that oxytocin administrated via the intranasal route, which is believed to provide a favorable pathway for the peptide into the central nervous system, provides benefit with respect to emotion recognition, positive and negative core symptoms, social cognitive measures, and neurocognition.

In one double-blind, placebo-controlled, crossover study, oxytocin was shown to improve emotion recognition, Bruno Averbeck, Ph.D., reported. In an initial experiment, 30 stable, medicated community-dwelling patients with schizophrenia and 29 control subjects matched for age and IQ completed an emotion discrimination task involving images of facial expressions representing specific emotions. Some images included a single emotion, and others were morphed images, depicting two commonly confused emotions such as surprise and fear.

Patients with schizophrenia were less able than controls to accurately recognize emotions using both unmorphed and morphed images, although both groups performed worse on identifying morphed emotions, said Dr. Averbeck of the National Institute of Mental Health.

In the crossover study, the effects of one 24-IU dose of oxytocin on the same emotion recognition task were measured in 21 patients with schizophrenia. Compared with performance without oxytocin, there was a 25% improvement in emotion recognition following oxytocin treatment, with improved recognition of certain emotions, such as happiness and sadness, but not others, such as surprise, he said (Psychol. Med. 2012;42:259-66).

A possible explanation for the improved performance on emotion recognition tasks following intranasal oxytocin administration is increased saccades to the eye region. A great deal of emotion is expressed through the eyes, and patients with schizophrenia are prone to avoidance of the eye region, Dr. Averbeck explained, noting that prior studies in patients with autism have shown that oxytocin increases saccades and emotion recognition.

In two other proof-of-concept trials, intranasal oxytocin was found to significantly reduce both positive and negative schizophrenia symptoms, and to improve social dysfunction.

A team of researchers at the University of California, San Diego (UCSD), conducted one of the studies – a randomized, placebo-controlled crossover trial of 15 adult patients with residual symptoms despite therapy. In the trial, either placebo or intranasal oxytocin, taken daily for 3 weeks and titrated to 40 IU (5 sprays) twice daily, was given in addition to stable doses of antipsychotic medication. The order of placebo and oxytocin was randomly assigned with a 1-week washout between treatments (Biol. Psychiatry 2010;68:678-80).

Oxytocin treatment for 3 weeks significantly reduced scores on the Positive and Negative Symptoms Scale (PANSS), with a difference of 5.46 points between groups on total scores. Clinical Global Impression-Improvement Scale (CGI-I) scores also were significantly improved in the treatment group, compared with placebo after 3 weeks of treatment, said Dr. David Feifel of UCSD, who led the study.

The findings support those of prior studies that also have demonstrated antipsychotic effects of oxytocin, and which have suggested oxytocin’s ability to ameliorate the symptoms of schizophrenia, he said.

In a separate proof-of-concept study, a team of researchers at the University of North Carolina, Chapel Hill (UNC), also found that after controlling for baseline measures, oxytocin treatment was associated with significantly greater declines in PANSS total scores, compared with placebo (least squares mean differences of 70.56 vs. 77.21), and with trends toward significantly greater declines vs. placebo in PANSS general subscale scores (least squares mean differences of 34.34 vs. 38.26).

In that 14-day parallel-arm study, led by Dr. Cort A. Pedersen of UNC, 14 adult patients were treated with 24 IU of intranasal oxytocin twice daily in addition to their stable regimens of antipsychotic medication, and 11 received placebo.

In both of these proof-of-concept studies, intranasal oxytocin was well tolerated, and also produced improvement on highly relevant secondary measures.

For example, in the UCSD study, oxytocin treatment was associated with significant improvement, compared with placebo, on California Verbal Learning Test scores on total recall, short-delay free recall, short-delay cued recall, total repetitions, and total recall discriminability.

In the UNC study, oxytocin treatment was associated with significant improvement in accurate identification of third-order false belief in the Brüne Theory of Mind Test (an evaluation of the ability to understand others’ thoughts and feelings). There also was a trend toward more accurate identification of second-order false belief and deception, and in the ability to rate faces as less untrustworthy. "None of these measures changed significantly in the placebo group," Dr. Pedersen said.

The improvements in social functioning are of note, because this is an aspect of schizophrenia that is a major cause of disability, and which tends to respond poorly to antipsychotic medications, according to Dr. Pedersen. The improvement seen with respect to neurocognition might further improve social and general functioning in patients with schizophrenia, he added.

Not all recent studies of oxytocin in schizophrenia have resulted in positive findings. In fact, a third proof-of-concept study by Dr. Kelly and her colleague, Dr. Mary Lee of the National Institute on Drug Abuse, did not demonstrate significant differences between oxytocin and placebo on many of the measures used in the two positive proof-of-concept studies. Thus, it remains unclear whether higher doses and longer duration of treatment would improve outcomes.

"The exciting thing is that these questions will hopefully be answered in several ongoing trials with higher doses," Dr. Feifel said, noting that one trial currently underway is evaluating doses ranging from 40 IU to 160 IU given for longer durations.

Dr. Pederson noted that he "won’t be surprised at all if [treatment with oxytocin] augments nonpharmacologic interventions such as social, cognitive, and neurocognitive training."

"Also, it may be more effective if treatment starts early in the course of disease rather than after a patient has been sick for decades," he said.

Dr. Kelly disclosed a financial relationship with Bristol-Myers Squibb. Dr. Pedersen disclosed holding a U.S. Provisional Patent Application, and receiving research support from the Foundation of Hope for Research and Treatment of Mental Illness and from the Stanley Medical Research Institute.

PHOENIX – Interest in the use of intranasal oxytocin for the treatment of psychiatric disorders has expanded in recent years, and several new studies suggest that it may have benefit in patients with schizophrenia.

The neuropeptide, which is associated with a wide variety of social behaviors in diverse species, may be particularly suited for treating schizophrenia, Deanna Kelly, Pharm.D., said during a symposium at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

"Schizophrenia is a disorder that is associated with a spectrum of social and emotional deficits, such as impaired perception of emotions, impaired social cue perception, and biased reasoning about certain types of social information. It is also a thought disorder associated with anxiety and mistrust," said Dr. Kelly of the University of Maryland, Baltimore.

It is well established that oxytocin regulates many of these factors, and compelling evidence suggests the oxytocin system is dysregulated in patients with schizophrenia.

Emerging clinical data demonstrate that oxytocin administrated via the intranasal route, which is believed to provide a favorable pathway for the peptide into the central nervous system, provides benefit with respect to emotion recognition, positive and negative core symptoms, social cognitive measures, and neurocognition.

In one double-blind, placebo-controlled, crossover study, oxytocin was shown to improve emotion recognition, Bruno Averbeck, Ph.D., reported. In an initial experiment, 30 stable, medicated community-dwelling patients with schizophrenia and 29 control subjects matched for age and IQ completed an emotion discrimination task involving images of facial expressions representing specific emotions. Some images included a single emotion, and others were morphed images, depicting two commonly confused emotions such as surprise and fear.

Patients with schizophrenia were less able than controls to accurately recognize emotions using both unmorphed and morphed images, although both groups performed worse on identifying morphed emotions, said Dr. Averbeck of the National Institute of Mental Health.

In the crossover study, the effects of one 24-IU dose of oxytocin on the same emotion recognition task were measured in 21 patients with schizophrenia. Compared with performance without oxytocin, there was a 25% improvement in emotion recognition following oxytocin treatment, with improved recognition of certain emotions, such as happiness and sadness, but not others, such as surprise, he said (Psychol. Med. 2012;42:259-66).

A possible explanation for the improved performance on emotion recognition tasks following intranasal oxytocin administration is increased saccades to the eye region. A great deal of emotion is expressed through the eyes, and patients with schizophrenia are prone to avoidance of the eye region, Dr. Averbeck explained, noting that prior studies in patients with autism have shown that oxytocin increases saccades and emotion recognition.

In two other proof-of-concept trials, intranasal oxytocin was found to significantly reduce both positive and negative schizophrenia symptoms, and to improve social dysfunction.

A team of researchers at the University of California, San Diego (UCSD), conducted one of the studies – a randomized, placebo-controlled crossover trial of 15 adult patients with residual symptoms despite therapy. In the trial, either placebo or intranasal oxytocin, taken daily for 3 weeks and titrated to 40 IU (5 sprays) twice daily, was given in addition to stable doses of antipsychotic medication. The order of placebo and oxytocin was randomly assigned with a 1-week washout between treatments (Biol. Psychiatry 2010;68:678-80).

Oxytocin treatment for 3 weeks significantly reduced scores on the Positive and Negative Symptoms Scale (PANSS), with a difference of 5.46 points between groups on total scores. Clinical Global Impression-Improvement Scale (CGI-I) scores also were significantly improved in the treatment group, compared with placebo after 3 weeks of treatment, said Dr. David Feifel of UCSD, who led the study.

The findings support those of prior studies that also have demonstrated antipsychotic effects of oxytocin, and which have suggested oxytocin’s ability to ameliorate the symptoms of schizophrenia, he said.

In a separate proof-of-concept study, a team of researchers at the University of North Carolina, Chapel Hill (UNC), also found that after controlling for baseline measures, oxytocin treatment was associated with significantly greater declines in PANSS total scores, compared with placebo (least squares mean differences of 70.56 vs. 77.21), and with trends toward significantly greater declines vs. placebo in PANSS general subscale scores (least squares mean differences of 34.34 vs. 38.26).

In that 14-day parallel-arm study, led by Dr. Cort A. Pedersen of UNC, 14 adult patients were treated with 24 IU of intranasal oxytocin twice daily in addition to their stable regimens of antipsychotic medication, and 11 received placebo.

In both of these proof-of-concept studies, intranasal oxytocin was well tolerated, and also produced improvement on highly relevant secondary measures.

For example, in the UCSD study, oxytocin treatment was associated with significant improvement, compared with placebo, on California Verbal Learning Test scores on total recall, short-delay free recall, short-delay cued recall, total repetitions, and total recall discriminability.

In the UNC study, oxytocin treatment was associated with significant improvement in accurate identification of third-order false belief in the Brüne Theory of Mind Test (an evaluation of the ability to understand others’ thoughts and feelings). There also was a trend toward more accurate identification of second-order false belief and deception, and in the ability to rate faces as less untrustworthy. "None of these measures changed significantly in the placebo group," Dr. Pedersen said.

The improvements in social functioning are of note, because this is an aspect of schizophrenia that is a major cause of disability, and which tends to respond poorly to antipsychotic medications, according to Dr. Pedersen. The improvement seen with respect to neurocognition might further improve social and general functioning in patients with schizophrenia, he added.

Not all recent studies of oxytocin in schizophrenia have resulted in positive findings. In fact, a third proof-of-concept study by Dr. Kelly and her colleague, Dr. Mary Lee of the National Institute on Drug Abuse, did not demonstrate significant differences between oxytocin and placebo on many of the measures used in the two positive proof-of-concept studies. Thus, it remains unclear whether higher doses and longer duration of treatment would improve outcomes.

"The exciting thing is that these questions will hopefully be answered in several ongoing trials with higher doses," Dr. Feifel said, noting that one trial currently underway is evaluating doses ranging from 40 IU to 160 IU given for longer durations.

Dr. Pederson noted that he "won’t be surprised at all if [treatment with oxytocin] augments nonpharmacologic interventions such as social, cognitive, and neurocognitive training."

"Also, it may be more effective if treatment starts early in the course of disease rather than after a patient has been sick for decades," he said.

Dr. Kelly disclosed a financial relationship with Bristol-Myers Squibb. Dr. Pedersen disclosed holding a U.S. Provisional Patent Application, and receiving research support from the Foundation of Hope for Research and Treatment of Mental Illness and from the Stanley Medical Research Institute.

PHOENIX – Estrogen exposure across the lifespan appears to be associated with risk of depression during the menopausal transition, according to findings from the Study of Women's Health Across the Nation, or SWAN.

Specifically, a longer total duration of estradiol exposure was found to be protective against depression during the menopausal transition, Dr. Claudio N. Soares reported at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

"What the data show is that for each year of increased premenopausal exposure to estrogen, you reduce by 15% the risk for developing depression after entering the menopausal transition. So the longer the exposure, the lower the risk," said Dr. Soares of McMaster University, Hamilton, Ont.

The menopausal transition has been shown in numerous studies to be a time of increased depression risk, and endocrinologic factors have been hypothesized as contributing to vulnerability to depression. It has remained unclear, however, why some women are at increased risk compared with others.

Studies have shown that estrogen exposure can improve depression, but the question of whether estrogen exposure prior to the menopausal transition would affect depression risk during the transition had not been addressed, Dr. Soares noted.

To assess factors – including lifetime exposure to estrogen (based on the time from age at menarche to the age at menopause) – that might contribute to depression risk during this reproductive phase, Dr. Soares and his colleagues analyzed data from more than 1,200 women who participated in SWAN, a seven-site, longitudinal, epidemiologic study designed to examine the physical, biological, and psychological changes that women undergo during their middle and menopausal years.

The average duration of estradiol exposure in the women (who were aged 42-52 years at study entry and who have been followed for nearly 10 years) was about 36 years. A longer duration of exposure prior to the menopausal transition was associated with a lower risk of having a score of less than 16 on the CES-D (Center for Epidemiologic Studies-Depression) scale during the transition (hazard ratio, 0.847 after adjustment for numerous factors, including age, ethnicity, education, study site, premenopausal depression, current and ever antidepressant use, baseline smoking, and time in study), Dr. Soares said.

"The next question is, what is happening during that time of exposure that could be exacerbating risk?" he said, noting, for example, that some interesting data show that oral contraceptive use may affect depression exacerbations. When investigators looked at oral contraceptive use as a continuous variable in this study, it was shown to be associated with an even greater protective effect.

However, other factors also could modulate exposure to estrogen exposure, such as the number of pregnancies and duration of breastfeeding. The next step of the analysis will look at such interactions, he said.

Thus far, the findings indicate that the relationship between depression and the menopausal transition is complex and is associated with both current and historic reproductive endocrinology, Dr. Soares said.

This study was supported by the North American Menopause Society. SWAN was supported by grants from the National Institutes of Health. Dr. Soares disclosed financial relationships with AstraZeneca, Bristol-Myers Squibb, CIHR, Eli Lilly, Lundbeck, Moven Pharmaceuticals, NARSAD, and Pfizer, but reported having no conflicts with respect to this study.

PHOENIX – Estrogen exposure across the lifespan appears to be associated with risk of depression during the menopausal transition, according to findings from the Study of Women's Health Across the Nation, or SWAN.

Specifically, a longer total duration of estradiol exposure was found to be protective against depression during the menopausal transition, Dr. Claudio N. Soares reported at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

"What the data show is that for each year of increased premenopausal exposure to estrogen, you reduce by 15% the risk for developing depression after entering the menopausal transition. So the longer the exposure, the lower the risk," said Dr. Soares of McMaster University, Hamilton, Ont.

The menopausal transition has been shown in numerous studies to be a time of increased depression risk, and endocrinologic factors have been hypothesized as contributing to vulnerability to depression. It has remained unclear, however, why some women are at increased risk compared with others.

Studies have shown that estrogen exposure can improve depression, but the question of whether estrogen exposure prior to the menopausal transition would affect depression risk during the transition had not been addressed, Dr. Soares noted.

To assess factors – including lifetime exposure to estrogen (based on the time from age at menarche to the age at menopause) – that might contribute to depression risk during this reproductive phase, Dr. Soares and his colleagues analyzed data from more than 1,200 women who participated in SWAN, a seven-site, longitudinal, epidemiologic study designed to examine the physical, biological, and psychological changes that women undergo during their middle and menopausal years.

The average duration of estradiol exposure in the women (who were aged 42-52 years at study entry and who have been followed for nearly 10 years) was about 36 years. A longer duration of exposure prior to the menopausal transition was associated with a lower risk of having a score of less than 16 on the CES-D (Center for Epidemiologic Studies-Depression) scale during the transition (hazard ratio, 0.847 after adjustment for numerous factors, including age, ethnicity, education, study site, premenopausal depression, current and ever antidepressant use, baseline smoking, and time in study), Dr. Soares said.

"The next question is, what is happening during that time of exposure that could be exacerbating risk?" he said, noting, for example, that some interesting data show that oral contraceptive use may affect depression exacerbations. When investigators looked at oral contraceptive use as a continuous variable in this study, it was shown to be associated with an even greater protective effect.

However, other factors also could modulate exposure to estrogen exposure, such as the number of pregnancies and duration of breastfeeding. The next step of the analysis will look at such interactions, he said.

Thus far, the findings indicate that the relationship between depression and the menopausal transition is complex and is associated with both current and historic reproductive endocrinology, Dr. Soares said.

This study was supported by the North American Menopause Society. SWAN was supported by grants from the National Institutes of Health. Dr. Soares disclosed financial relationships with AstraZeneca, Bristol-Myers Squibb, CIHR, Eli Lilly, Lundbeck, Moven Pharmaceuticals, NARSAD, and Pfizer, but reported having no conflicts with respect to this study.

PHOENIX – Estrogen exposure across the lifespan appears to be associated with risk of depression during the menopausal transition, according to findings from the Study of Women's Health Across the Nation, or SWAN.

Specifically, a longer total duration of estradiol exposure was found to be protective against depression during the menopausal transition, Dr. Claudio N. Soares reported at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

"What the data show is that for each year of increased premenopausal exposure to estrogen, you reduce by 15% the risk for developing depression after entering the menopausal transition. So the longer the exposure, the lower the risk," said Dr. Soares of McMaster University, Hamilton, Ont.

The menopausal transition has been shown in numerous studies to be a time of increased depression risk, and endocrinologic factors have been hypothesized as contributing to vulnerability to depression. It has remained unclear, however, why some women are at increased risk compared with others.

Studies have shown that estrogen exposure can improve depression, but the question of whether estrogen exposure prior to the menopausal transition would affect depression risk during the transition had not been addressed, Dr. Soares noted.

To assess factors – including lifetime exposure to estrogen (based on the time from age at menarche to the age at menopause) – that might contribute to depression risk during this reproductive phase, Dr. Soares and his colleagues analyzed data from more than 1,200 women who participated in SWAN, a seven-site, longitudinal, epidemiologic study designed to examine the physical, biological, and psychological changes that women undergo during their middle and menopausal years.

The average duration of estradiol exposure in the women (who were aged 42-52 years at study entry and who have been followed for nearly 10 years) was about 36 years. A longer duration of exposure prior to the menopausal transition was associated with a lower risk of having a score of less than 16 on the CES-D (Center for Epidemiologic Studies-Depression) scale during the transition (hazard ratio, 0.847 after adjustment for numerous factors, including age, ethnicity, education, study site, premenopausal depression, current and ever antidepressant use, baseline smoking, and time in study), Dr. Soares said.

"The next question is, what is happening during that time of exposure that could be exacerbating risk?" he said, noting, for example, that some interesting data show that oral contraceptive use may affect depression exacerbations. When investigators looked at oral contraceptive use as a continuous variable in this study, it was shown to be associated with an even greater protective effect.

However, other factors also could modulate exposure to estrogen exposure, such as the number of pregnancies and duration of breastfeeding. The next step of the analysis will look at such interactions, he said.

Thus far, the findings indicate that the relationship between depression and the menopausal transition is complex and is associated with both current and historic reproductive endocrinology, Dr. Soares said.

This study was supported by the North American Menopause Society. SWAN was supported by grants from the National Institutes of Health. Dr. Soares disclosed financial relationships with AstraZeneca, Bristol-Myers Squibb, CIHR, Eli Lilly, Lundbeck, Moven Pharmaceuticals, NARSAD, and Pfizer, but reported having no conflicts with respect to this study.

PHOENIX – The burden of comorbid medical illness is high, and is linked to increased prescribing of psychotropic drugs, in patients with bipolar I and II disorder, based on findings from the Lithium Treatment – Moderate Dose Use Study, or LiTMUS.

Clinically significant medical burden, defined by a score of 4 or more on the Cumulative Illness Rating Scale (CIRS), was present in 139 of 264 LiTMUS participants with available CIRS data. A score of 4 or higher on the 14-point scale indicates that a patient has at least two moderately disabling medical problems requiring first-line treatment, Dr. David E. Kemp of Case Western Reserve University, Cleveland, and his colleagues reported in a poster. They presented their findings at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

The 139 patients with high medical comorbidity were significantly more likely than were those with low medical comorbidity to present in a current major depressive episode (71.3% vs. 57.8%), to have obsessive-compulsive disorder (14.4% vs. 5.6%), and to have previous mood episodes (66.5% vs. 37.7%), and previous manic or hypomanic episodes (34.9% vs. 18.3%), the investigators said.

Those with high medical comorbidity were also more likely to be female (61.9% vs. 50.4%) and to have previous depressive episodes (29.5% vs. 19.7%), although these measures did not reach statistical significance.

"Patients with high vs. low medical comorbidity burden experienced an average of 10 additional depressive episodes and 15 additional manic or hypomanic episodes over their lifetime," the investigators noted.

As for psychotropic medication use, those with high medical comorbidity were prescribed an average of 2.9 medications, compared with 2.3 for those with low medical comorbidity, a statistically significant difference, the investigators said.

The most common comorbid medical conditions in LiTMUS participants were migraines, hypertension, hyperlipidemia, and asthma, occurring in 24%, 17%, 15%, and 15% of study participants, respectively. The most common organ systems affected by medical comorbidity were the musculoskeletal, respiratory, and endocrine systems (in 33%, 27%, and 25% of participants, respectively).

Of note, hypertension and dyslipidemia were frequently underrecognized and undertreated in this population. Hypertension was diagnosed by a clinician in 44% of participants, but reported by only 17% of the patients; dyslipidemia was diagnosed by a clinician in 31% of participants, but reported by only 15%.

Additionally, 70% of the sample was overweight or obese. More males than females with bipolar I disorder were overweight, whereas more females than males with bipolar I disorder were obese. African Americans were the ethnic group with the highest rate (31%) of grade 2 obesity, defined as a body mass index of 35 kg/m² or greater, they noted.

LiTMUS was undertaken to estimate the prevalence and burden of general medical illnesses among patients with bipolar disorder and to identify the potential associations between those illnesses and the clinical features of bipolar disorder, the investigators said. Dr. Kemp and his colleagues explained that patients with bipolar disorder are known to have an increased risk for several general medical conditions, which contribute to an up to 30% shorter life expectancy in this population, compared with the general population.

Previous studies have identified links between cardiometabolic disorders and psychiatric illness severity suggestive of a genetic and pathophysiologic diathesis that predisposes vulnerable individuals to the concurrent development of mood symptoms and medical conditions, they said.

Participants were adults aged 18 years or older with bipolar I or II disorder and mood symptoms of at least mild severity that warranted a change in treatment. Having symptoms of at least mild severity was defined as a score of 3 or greater on the Clinical Global Impression Scale-Bipolar Version.

The findings reinforce the notion that bipolar disorder is associated with a high burden of comorbid medical illnesses, which appear to influence the course of the illness and psychotropic prescribing patterns, and they "highlight the multisystem involvement in bipolar disorder and the need for improved understanding of the relationships between psychiatric pathology and medical illness," the investigators concluded.

This study was funded by the National Institute of Mental Health. The authors had no disclosures.

PHOENIX – The burden of comorbid medical illness is high, and is linked to increased prescribing of psychotropic drugs, in patients with bipolar I and II disorder, based on findings from the Lithium Treatment – Moderate Dose Use Study, or LiTMUS.

Clinically significant medical burden, defined by a score of 4 or more on the Cumulative Illness Rating Scale (CIRS), was present in 139 of 264 LiTMUS participants with available CIRS data. A score of 4 or higher on the 14-point scale indicates that a patient has at least two moderately disabling medical problems requiring first-line treatment, Dr. David E. Kemp of Case Western Reserve University, Cleveland, and his colleagues reported in a poster. They presented their findings at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

The 139 patients with high medical comorbidity were significantly more likely than were those with low medical comorbidity to present in a current major depressive episode (71.3% vs. 57.8%), to have obsessive-compulsive disorder (14.4% vs. 5.6%), and to have previous mood episodes (66.5% vs. 37.7%), and previous manic or hypomanic episodes (34.9% vs. 18.3%), the investigators said.

Those with high medical comorbidity were also more likely to be female (61.9% vs. 50.4%) and to have previous depressive episodes (29.5% vs. 19.7%), although these measures did not reach statistical significance.

"Patients with high vs. low medical comorbidity burden experienced an average of 10 additional depressive episodes and 15 additional manic or hypomanic episodes over their lifetime," the investigators noted.

As for psychotropic medication use, those with high medical comorbidity were prescribed an average of 2.9 medications, compared with 2.3 for those with low medical comorbidity, a statistically significant difference, the investigators said.

The most common comorbid medical conditions in LiTMUS participants were migraines, hypertension, hyperlipidemia, and asthma, occurring in 24%, 17%, 15%, and 15% of study participants, respectively. The most common organ systems affected by medical comorbidity were the musculoskeletal, respiratory, and endocrine systems (in 33%, 27%, and 25% of participants, respectively).

Of note, hypertension and dyslipidemia were frequently underrecognized and undertreated in this population. Hypertension was diagnosed by a clinician in 44% of participants, but reported by only 17% of the patients; dyslipidemia was diagnosed by a clinician in 31% of participants, but reported by only 15%.

Additionally, 70% of the sample was overweight or obese. More males than females with bipolar I disorder were overweight, whereas more females than males with bipolar I disorder were obese. African Americans were the ethnic group with the highest rate (31%) of grade 2 obesity, defined as a body mass index of 35 kg/m² or greater, they noted.

LiTMUS was undertaken to estimate the prevalence and burden of general medical illnesses among patients with bipolar disorder and to identify the potential associations between those illnesses and the clinical features of bipolar disorder, the investigators said. Dr. Kemp and his colleagues explained that patients with bipolar disorder are known to have an increased risk for several general medical conditions, which contribute to an up to 30% shorter life expectancy in this population, compared with the general population.

Previous studies have identified links between cardiometabolic disorders and psychiatric illness severity suggestive of a genetic and pathophysiologic diathesis that predisposes vulnerable individuals to the concurrent development of mood symptoms and medical conditions, they said.

Participants were adults aged 18 years or older with bipolar I or II disorder and mood symptoms of at least mild severity that warranted a change in treatment. Having symptoms of at least mild severity was defined as a score of 3 or greater on the Clinical Global Impression Scale-Bipolar Version.

The findings reinforce the notion that bipolar disorder is associated with a high burden of comorbid medical illnesses, which appear to influence the course of the illness and psychotropic prescribing patterns, and they "highlight the multisystem involvement in bipolar disorder and the need for improved understanding of the relationships between psychiatric pathology and medical illness," the investigators concluded.

This study was funded by the National Institute of Mental Health. The authors had no disclosures.

PHOENIX – The burden of comorbid medical illness is high, and is linked to increased prescribing of psychotropic drugs, in patients with bipolar I and II disorder, based on findings from the Lithium Treatment – Moderate Dose Use Study, or LiTMUS.

Clinically significant medical burden, defined by a score of 4 or more on the Cumulative Illness Rating Scale (CIRS), was present in 139 of 264 LiTMUS participants with available CIRS data. A score of 4 or higher on the 14-point scale indicates that a patient has at least two moderately disabling medical problems requiring first-line treatment, Dr. David E. Kemp of Case Western Reserve University, Cleveland, and his colleagues reported in a poster. They presented their findings at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

The 139 patients with high medical comorbidity were significantly more likely than were those with low medical comorbidity to present in a current major depressive episode (71.3% vs. 57.8%), to have obsessive-compulsive disorder (14.4% vs. 5.6%), and to have previous mood episodes (66.5% vs. 37.7%), and previous manic or hypomanic episodes (34.9% vs. 18.3%), the investigators said.

Those with high medical comorbidity were also more likely to be female (61.9% vs. 50.4%) and to have previous depressive episodes (29.5% vs. 19.7%), although these measures did not reach statistical significance.

"Patients with high vs. low medical comorbidity burden experienced an average of 10 additional depressive episodes and 15 additional manic or hypomanic episodes over their lifetime," the investigators noted.

As for psychotropic medication use, those with high medical comorbidity were prescribed an average of 2.9 medications, compared with 2.3 for those with low medical comorbidity, a statistically significant difference, the investigators said.

The most common comorbid medical conditions in LiTMUS participants were migraines, hypertension, hyperlipidemia, and asthma, occurring in 24%, 17%, 15%, and 15% of study participants, respectively. The most common organ systems affected by medical comorbidity were the musculoskeletal, respiratory, and endocrine systems (in 33%, 27%, and 25% of participants, respectively).

Of note, hypertension and dyslipidemia were frequently underrecognized and undertreated in this population. Hypertension was diagnosed by a clinician in 44% of participants, but reported by only 17% of the patients; dyslipidemia was diagnosed by a clinician in 31% of participants, but reported by only 15%.

Additionally, 70% of the sample was overweight or obese. More males than females with bipolar I disorder were overweight, whereas more females than males with bipolar I disorder were obese. African Americans were the ethnic group with the highest rate (31%) of grade 2 obesity, defined as a body mass index of 35 kg/m² or greater, they noted.

LiTMUS was undertaken to estimate the prevalence and burden of general medical illnesses among patients with bipolar disorder and to identify the potential associations between those illnesses and the clinical features of bipolar disorder, the investigators said. Dr. Kemp and his colleagues explained that patients with bipolar disorder are known to have an increased risk for several general medical conditions, which contribute to an up to 30% shorter life expectancy in this population, compared with the general population.

Previous studies have identified links between cardiometabolic disorders and psychiatric illness severity suggestive of a genetic and pathophysiologic diathesis that predisposes vulnerable individuals to the concurrent development of mood symptoms and medical conditions, they said.

Participants were adults aged 18 years or older with bipolar I or II disorder and mood symptoms of at least mild severity that warranted a change in treatment. Having symptoms of at least mild severity was defined as a score of 3 or greater on the Clinical Global Impression Scale-Bipolar Version.

The findings reinforce the notion that bipolar disorder is associated with a high burden of comorbid medical illnesses, which appear to influence the course of the illness and psychotropic prescribing patterns, and they "highlight the multisystem involvement in bipolar disorder and the need for improved understanding of the relationships between psychiatric pathology and medical illness," the investigators concluded.

This study was funded by the National Institute of Mental Health. The authors had no disclosures.

PHOENIX  – L-Methylfolate represents an effective and well-tolerated adjunctive therapy for patients with major depressive disorder who fail to respond adequately to treatment with selective serotonin reuptake inhibitors – particularly those patients with certain biomarkers and genotypes associated with metabolic dysfunction.

The folate derivative, which is categorized as a trimonoamine modulator, was shown in a 2011 double-blind, placebo-controlled, parallel-sequential study of 75 patients with SSRI-resistant major depressive disorder to be superior to placebo as an adjunctive therapy when given at a dose of 15 mg/day.

In that study, the pooled difference in response rates on the 17-item Hamilton Depression Rating Scale (HDRS-17) after 30 days between patients who received adjunctive L-methylfolate and those who received SSRI therapy plus placebo was 17.7%, Dr. George I. Papakostas, one of the study authors, said at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

The pooled differences in mean change on the HDRS-17 and HDRS-28 also differed significantly between the groups, indicating greater improvement in depressive symptoms in the L-methylfolate group, he reported.

Greater improvement also was demonstrated on secondary outcome measures, including changes in scores on the patient-rated Quick Inventory of Depressive Symptomatology (QIDS-SR) and Clinical Global Impressions-Severity Scale (CGI-S), in those who received L-methylfolate, said Dr. Papakostas of Massachusetts General Hospital, Boston.

In a new analysis looking at secondary genomic and biomarker end points and their association with treatment effect, it was noted that effects were similar in patients with baseline L-methylfolate levels below and above the median. However, a greater treatment effect was observed in patients with an allelic variant in the methylenetetrahydrofolate reductase (MTHFR) C677T genotype. There was a difference in mean change in HDRS-28 of –3.75 for those with the "t" allele, compared with –1.99 for the "cc" allele, Dr. Papakostas reported.

Furthermore, patients with a body mass index of 30 kg/m² or greater also experienced a significantly greater reduction in depressive symptoms following treatment with L-methylfolate – a difference in mean change in HDRS-28 of –4.66.

Study participants were outpatients who had no response, or only a partial response, to SSRIs. The 60-day multicenter trial used a novel sequential parallel comparison design, and was thus divided into two 30-day phases. In addition to their SSRI treatment, patients were randomized to receive either adjunctive L-methylfolate for 60 days, placebo for 30 days followed by L-methylfolate for 30 days, or placebo for 60 days.

The findings suggest that biomarkers could play a role in individualizing L-methylfolate therapy in depressed patients, Dr. Papakostas said.

Findings from another post hoc analysis of the data, which were presented in a poster at the meeting by Dr. Papakostas and Dr. Stephen M. Stahl of the Neuroscience Education Institute in Carlsbad, Calif., suggest that L-methylfolate improves outcomes by addressing metabolic imbalances associated with elevated BMI, as well as with inflammation.

BMI and inflammatory markers such as C-reactive protein have been shown to be independently associated with MDD, and increased body weight is associated with decreased response to antidepressants, the authors noted.

For this analysis, they assessed the effect of L-methylfolate as an adjunct to SSRI treatment on the Maier subscale of the HDRS and correlations with inflammatory biomarkers.

The mean change on the Maier subscale was –3.3 for patients who received L-methylfolate, compared with –1.5 for those who received placebo, based on pooled data. The mean improvement in symptoms also was significantly greater in the L-methylfolate patients versus the placebo patients when BMI was 30 kg/m² or greater (–7.4 vs. –2.4, respectively), and when elevated baseline high-sensitivity C-reactive protein (hsCRP) was above the median of 2.25 mg/L (–7.7 vs. –3.7, respectively). Other biomarkers for which significant associations were seen included S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) less than 2.71 and 4-hydroxynonenal (4-HNE) of 3.28 mcg/mL or greater.

Stratification by genotype showed that the pooled mean change from baseline with L-methylfolate vs. placebo was significantly greater in patients with the 5-methyltetrahydrofolate methyltransferase (MTR) 2756 AG/GG or the MTR reductase (MTRR) 66 AG/GG genotype, the investigators said, noting that a trend toward significance was seen for the MTHFR 677CT/TT genotype.

"Improvement in core symptoms on the Maier subscale was significantly correlated with BMI of 30 kg/m² or greater, 4-HNE greater than the study median, SAM/SAH ratio less than the study median, and hsCRP less than the study median. Changes in core symptoms on the Maier subscale also were significantly associated with the MTR 2756 AG/GG genotype," they wrote in the poster.

"Effects on biomarkers of metabolic dysregulation may explain the significant impact of L-methylfolate on core symptoms of depression in patients with SSRI-resistant MDD," the investigators concluded.

The findings represent a "consistent signal suggesting that something is going on with respect to the metabolic, inflammatory, and oxidative profile of some patients that renders them ... particularly susceptible to the therapeutic effects of L-methylfolate as adjunctive therapy above and beyond placebo," Dr. Papakostas said, stressing that confirmatory trials are needed.

These studies were supported by a grant from PamLab. Dr. Papakostas and Dr. Stahl disclosed financial relationships with numerous pharmaceutical companies.

PHOENIX  – L-Methylfolate represents an effective and well-tolerated adjunctive therapy for patients with major depressive disorder who fail to respond adequately to treatment with selective serotonin reuptake inhibitors – particularly those patients with certain biomarkers and genotypes associated with metabolic dysfunction.

The folate derivative, which is categorized as a trimonoamine modulator, was shown in a 2011 double-blind, placebo-controlled, parallel-sequential study of 75 patients with SSRI-resistant major depressive disorder to be superior to placebo as an adjunctive therapy when given at a dose of 15 mg/day.

In that study, the pooled difference in response rates on the 17-item Hamilton Depression Rating Scale (HDRS-17) after 30 days between patients who received adjunctive L-methylfolate and those who received SSRI therapy plus placebo was 17.7%, Dr. George I. Papakostas, one of the study authors, said at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

The pooled differences in mean change on the HDRS-17 and HDRS-28 also differed significantly between the groups, indicating greater improvement in depressive symptoms in the L-methylfolate group, he reported.

Greater improvement also was demonstrated on secondary outcome measures, including changes in scores on the patient-rated Quick Inventory of Depressive Symptomatology (QIDS-SR) and Clinical Global Impressions-Severity Scale (CGI-S), in those who received L-methylfolate, said Dr. Papakostas of Massachusetts General Hospital, Boston.

In a new analysis looking at secondary genomic and biomarker end points and their association with treatment effect, it was noted that effects were similar in patients with baseline L-methylfolate levels below and above the median. However, a greater treatment effect was observed in patients with an allelic variant in the methylenetetrahydrofolate reductase (MTHFR) C677T genotype. There was a difference in mean change in HDRS-28 of –3.75 for those with the "t" allele, compared with –1.99 for the "cc" allele, Dr. Papakostas reported.

Furthermore, patients with a body mass index of 30 kg/m² or greater also experienced a significantly greater reduction in depressive symptoms following treatment with L-methylfolate – a difference in mean change in HDRS-28 of –4.66.

Study participants were outpatients who had no response, or only a partial response, to SSRIs. The 60-day multicenter trial used a novel sequential parallel comparison design, and was thus divided into two 30-day phases. In addition to their SSRI treatment, patients were randomized to receive either adjunctive L-methylfolate for 60 days, placebo for 30 days followed by L-methylfolate for 30 days, or placebo for 60 days.

The findings suggest that biomarkers could play a role in individualizing L-methylfolate therapy in depressed patients, Dr. Papakostas said.

Findings from another post hoc analysis of the data, which were presented in a poster at the meeting by Dr. Papakostas and Dr. Stephen M. Stahl of the Neuroscience Education Institute in Carlsbad, Calif., suggest that L-methylfolate improves outcomes by addressing metabolic imbalances associated with elevated BMI, as well as with inflammation.

BMI and inflammatory markers such as C-reactive protein have been shown to be independently associated with MDD, and increased body weight is associated with decreased response to antidepressants, the authors noted.

For this analysis, they assessed the effect of L-methylfolate as an adjunct to SSRI treatment on the Maier subscale of the HDRS and correlations with inflammatory biomarkers.

The mean change on the Maier subscale was –3.3 for patients who received L-methylfolate, compared with –1.5 for those who received placebo, based on pooled data. The mean improvement in symptoms also was significantly greater in the L-methylfolate patients versus the placebo patients when BMI was 30 kg/m² or greater (–7.4 vs. –2.4, respectively), and when elevated baseline high-sensitivity C-reactive protein (hsCRP) was above the median of 2.25 mg/L (–7.7 vs. –3.7, respectively). Other biomarkers for which significant associations were seen included S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) less than 2.71 and 4-hydroxynonenal (4-HNE) of 3.28 mcg/mL or greater.

Stratification by genotype showed that the pooled mean change from baseline with L-methylfolate vs. placebo was significantly greater in patients with the 5-methyltetrahydrofolate methyltransferase (MTR) 2756 AG/GG or the MTR reductase (MTRR) 66 AG/GG genotype, the investigators said, noting that a trend toward significance was seen for the MTHFR 677CT/TT genotype.

"Improvement in core symptoms on the Maier subscale was significantly correlated with BMI of 30 kg/m² or greater, 4-HNE greater than the study median, SAM/SAH ratio less than the study median, and hsCRP less than the study median. Changes in core symptoms on the Maier subscale also were significantly associated with the MTR 2756 AG/GG genotype," they wrote in the poster.

"Effects on biomarkers of metabolic dysregulation may explain the significant impact of L-methylfolate on core symptoms of depression in patients with SSRI-resistant MDD," the investigators concluded.

The findings represent a "consistent signal suggesting that something is going on with respect to the metabolic, inflammatory, and oxidative profile of some patients that renders them ... particularly susceptible to the therapeutic effects of L-methylfolate as adjunctive therapy above and beyond placebo," Dr. Papakostas said, stressing that confirmatory trials are needed.

These studies were supported by a grant from PamLab. Dr. Papakostas and Dr. Stahl disclosed financial relationships with numerous pharmaceutical companies.

PHOENIX  – L-Methylfolate represents an effective and well-tolerated adjunctive therapy for patients with major depressive disorder who fail to respond adequately to treatment with selective serotonin reuptake inhibitors – particularly those patients with certain biomarkers and genotypes associated with metabolic dysfunction.

The folate derivative, which is categorized as a trimonoamine modulator, was shown in a 2011 double-blind, placebo-controlled, parallel-sequential study of 75 patients with SSRI-resistant major depressive disorder to be superior to placebo as an adjunctive therapy when given at a dose of 15 mg/day.

In that study, the pooled difference in response rates on the 17-item Hamilton Depression Rating Scale (HDRS-17) after 30 days between patients who received adjunctive L-methylfolate and those who received SSRI therapy plus placebo was 17.7%, Dr. George I. Papakostas, one of the study authors, said at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

The pooled differences in mean change on the HDRS-17 and HDRS-28 also differed significantly between the groups, indicating greater improvement in depressive symptoms in the L-methylfolate group, he reported.

Greater improvement also was demonstrated on secondary outcome measures, including changes in scores on the patient-rated Quick Inventory of Depressive Symptomatology (QIDS-SR) and Clinical Global Impressions-Severity Scale (CGI-S), in those who received L-methylfolate, said Dr. Papakostas of Massachusetts General Hospital, Boston.

In a new analysis looking at secondary genomic and biomarker end points and their association with treatment effect, it was noted that effects were similar in patients with baseline L-methylfolate levels below and above the median. However, a greater treatment effect was observed in patients with an allelic variant in the methylenetetrahydrofolate reductase (MTHFR) C677T genotype. There was a difference in mean change in HDRS-28 of –3.75 for those with the "t" allele, compared with –1.99 for the "cc" allele, Dr. Papakostas reported.

Furthermore, patients with a body mass index of 30 kg/m² or greater also experienced a significantly greater reduction in depressive symptoms following treatment with L-methylfolate – a difference in mean change in HDRS-28 of –4.66.

Study participants were outpatients who had no response, or only a partial response, to SSRIs. The 60-day multicenter trial used a novel sequential parallel comparison design, and was thus divided into two 30-day phases. In addition to their SSRI treatment, patients were randomized to receive either adjunctive L-methylfolate for 60 days, placebo for 30 days followed by L-methylfolate for 30 days, or placebo for 60 days.

The findings suggest that biomarkers could play a role in individualizing L-methylfolate therapy in depressed patients, Dr. Papakostas said.

Findings from another post hoc analysis of the data, which were presented in a poster at the meeting by Dr. Papakostas and Dr. Stephen M. Stahl of the Neuroscience Education Institute in Carlsbad, Calif., suggest that L-methylfolate improves outcomes by addressing metabolic imbalances associated with elevated BMI, as well as with inflammation.

BMI and inflammatory markers such as C-reactive protein have been shown to be independently associated with MDD, and increased body weight is associated with decreased response to antidepressants, the authors noted.

For this analysis, they assessed the effect of L-methylfolate as an adjunct to SSRI treatment on the Maier subscale of the HDRS and correlations with inflammatory biomarkers.

The mean change on the Maier subscale was –3.3 for patients who received L-methylfolate, compared with –1.5 for those who received placebo, based on pooled data. The mean improvement in symptoms also was significantly greater in the L-methylfolate patients versus the placebo patients when BMI was 30 kg/m² or greater (–7.4 vs. –2.4, respectively), and when elevated baseline high-sensitivity C-reactive protein (hsCRP) was above the median of 2.25 mg/L (–7.7 vs. –3.7, respectively). Other biomarkers for which significant associations were seen included S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) less than 2.71 and 4-hydroxynonenal (4-HNE) of 3.28 mcg/mL or greater.

Stratification by genotype showed that the pooled mean change from baseline with L-methylfolate vs. placebo was significantly greater in patients with the 5-methyltetrahydrofolate methyltransferase (MTR) 2756 AG/GG or the MTR reductase (MTRR) 66 AG/GG genotype, the investigators said, noting that a trend toward significance was seen for the MTHFR 677CT/TT genotype.

"Improvement in core symptoms on the Maier subscale was significantly correlated with BMI of 30 kg/m² or greater, 4-HNE greater than the study median, SAM/SAH ratio less than the study median, and hsCRP less than the study median. Changes in core symptoms on the Maier subscale also were significantly associated with the MTR 2756 AG/GG genotype," they wrote in the poster.

"Effects on biomarkers of metabolic dysregulation may explain the significant impact of L-methylfolate on core symptoms of depression in patients with SSRI-resistant MDD," the investigators concluded.

The findings represent a "consistent signal suggesting that something is going on with respect to the metabolic, inflammatory, and oxidative profile of some patients that renders them ... particularly susceptible to the therapeutic effects of L-methylfolate as adjunctive therapy above and beyond placebo," Dr. Papakostas said, stressing that confirmatory trials are needed.

These studies were supported by a grant from PamLab. Dr. Papakostas and Dr. Stahl disclosed financial relationships with numerous pharmaceutical companies.

PHOENIX – The use of opioids for treating depression is limited by abuse potential, but an investigational drug is showing promise in early clinical trials by providing the benefits of opioids while counteracting the mu opioid agonism thought to contribute to abuse potential.

ALKS 5461 combines buprenorphine, which is a partial mu agonist, and ALKS 33, a novel counteracting mu antagonist, Dr. Elliot W. Ehrich of Alkermes PLC, Waltham, Mass., reported at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

ALKS 33 was designed to provide minimally metabolized, highly potent, and sublingually bioavailable mu antagonism to allow for effective coformulation of the two agents. In an initial clinical trial, ALKS 33 at 10-mg and 20-mg oral doses completely blocked mu agonist effects of serial pulses of remifentanil in opioid-experienced volunteers. The effects were assessed by both physiologic measures such as pupilometry and subjective measures such as visual analogue scale assessment of drug liking and drug high.

"Hopefully (the findings) will ultimately enable broad utilization of opioid modulation in psychiatric disorders."

The duration of blockade was greater than 24 hours following a single dose, Dr. Ehrich said. Subsequently, a drug-drug interaction study was performed to identify the ALKS 33 and buprenorphine ratio that would provide complete blockade. The findings showed that when administered together with 8 mg of buprenorphine, ALKS 33 caused partial attenuation of mu effects at a 1-mg dose, and complete blockade of mu effects at doses of 4 mg or greater.

In addition, a double-blind, placebo-controlled pilot study showed rapid efficacy of ALKS 5461 in 32 patients with major depressive disorder who failed to respond adequately to treatment with selective serotonin reuptake inhibitors (SSRIs) or selective serotonin-norepinephrine reuptake inhibitors (SNRIs), he said.

Patients were randomized to receive daily sublingual treatment with ALKS 5461 at an 8:1 ratio of buprenorphine and ALKS 33, which provided partial blockade of buprenorphine mu agonist effects, or a 1:1 ratio, which provided complete blockade of the effects. Patients continued on their SSRI or SNRI treatments.

Based on outcomes using the Hamilton Depression Rating Scale (HAMD-17) and the Montgomery-Asberg Depression Rating Scale (MADRS), efficacy was seen with both dose ratios at 7 days.

"What was a little surprising to us was that we actually saw a greater reduction [in symptoms] with full vs. partial blockade," Dr. Ehrich said, adding that the patterns on MADRS scores were similar with both ratios, but "every patient on the full blockade ratio demonstrated a response."

Furthermore, treatment was well tolerated, he said. The most common adverse events were those typically seen with opioid treatment, including dizziness, nausea, vomiting, and sedation, which occurred more frequently with partial blockade.

These early findings suggest that the therapeutic effects of opioids in mood disorders can be decoupled from the mu agonist effects of drug high and euphoria, thereby "bringing the ‘opium cure’ into the 21st century in the context of the most pharmacologically rational and responsible way, and in the context of data from controlled clinical trials," Dr. Ehrich said.

Indeed, ALKS 5461 may represent a new rapid-onset treatment approach for depression and other psychiatric disorders, such as addictive disorder, he said.

A phase II study of the agent is underway in patients with major depressive disorder, and a cocaine-interaction study is also underway.

"Hopefully (the findings) will ultimately enable broad utilization of opioid modulation in psychiatric disorders," he said.

The ALKS 5461 studies were funded in part by the National Institute on Drug Abuse. Dr. Ehrich is employed by Alkermes, which is developing ALKS 5461.

PHOENIX – The use of opioids for treating depression is limited by abuse potential, but an investigational drug is showing promise in early clinical trials by providing the benefits of opioids while counteracting the mu opioid agonism thought to contribute to abuse potential.

ALKS 5461 combines buprenorphine, which is a partial mu agonist, and ALKS 33, a novel counteracting mu antagonist, Dr. Elliot W. Ehrich of Alkermes PLC, Waltham, Mass., reported at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

ALKS 33 was designed to provide minimally metabolized, highly potent, and sublingually bioavailable mu antagonism to allow for effective coformulation of the two agents. In an initial clinical trial, ALKS 33 at 10-mg and 20-mg oral doses completely blocked mu agonist effects of serial pulses of remifentanil in opioid-experienced volunteers. The effects were assessed by both physiologic measures such as pupilometry and subjective measures such as visual analogue scale assessment of drug liking and drug high.

"Hopefully (the findings) will ultimately enable broad utilization of opioid modulation in psychiatric disorders."

The duration of blockade was greater than 24 hours following a single dose, Dr. Ehrich said. Subsequently, a drug-drug interaction study was performed to identify the ALKS 33 and buprenorphine ratio that would provide complete blockade. The findings showed that when administered together with 8 mg of buprenorphine, ALKS 33 caused partial attenuation of mu effects at a 1-mg dose, and complete blockade of mu effects at doses of 4 mg or greater.

In addition, a double-blind, placebo-controlled pilot study showed rapid efficacy of ALKS 5461 in 32 patients with major depressive disorder who failed to respond adequately to treatment with selective serotonin reuptake inhibitors (SSRIs) or selective serotonin-norepinephrine reuptake inhibitors (SNRIs), he said.

Patients were randomized to receive daily sublingual treatment with ALKS 5461 at an 8:1 ratio of buprenorphine and ALKS 33, which provided partial blockade of buprenorphine mu agonist effects, or a 1:1 ratio, which provided complete blockade of the effects. Patients continued on their SSRI or SNRI treatments.

Based on outcomes using the Hamilton Depression Rating Scale (HAMD-17) and the Montgomery-Asberg Depression Rating Scale (MADRS), efficacy was seen with both dose ratios at 7 days.

"What was a little surprising to us was that we actually saw a greater reduction [in symptoms] with full vs. partial blockade," Dr. Ehrich said, adding that the patterns on MADRS scores were similar with both ratios, but "every patient on the full blockade ratio demonstrated a response."

Furthermore, treatment was well tolerated, he said. The most common adverse events were those typically seen with opioid treatment, including dizziness, nausea, vomiting, and sedation, which occurred more frequently with partial blockade.

These early findings suggest that the therapeutic effects of opioids in mood disorders can be decoupled from the mu agonist effects of drug high and euphoria, thereby "bringing the ‘opium cure’ into the 21st century in the context of the most pharmacologically rational and responsible way, and in the context of data from controlled clinical trials," Dr. Ehrich said.

Indeed, ALKS 5461 may represent a new rapid-onset treatment approach for depression and other psychiatric disorders, such as addictive disorder, he said.

A phase II study of the agent is underway in patients with major depressive disorder, and a cocaine-interaction study is also underway.

"Hopefully (the findings) will ultimately enable broad utilization of opioid modulation in psychiatric disorders," he said.

The ALKS 5461 studies were funded in part by the National Institute on Drug Abuse. Dr. Ehrich is employed by Alkermes, which is developing ALKS 5461.

PHOENIX – The use of opioids for treating depression is limited by abuse potential, but an investigational drug is showing promise in early clinical trials by providing the benefits of opioids while counteracting the mu opioid agonism thought to contribute to abuse potential.

ALKS 5461 combines buprenorphine, which is a partial mu agonist, and ALKS 33, a novel counteracting mu antagonist, Dr. Elliot W. Ehrich of Alkermes PLC, Waltham, Mass., reported at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

ALKS 33 was designed to provide minimally metabolized, highly potent, and sublingually bioavailable mu antagonism to allow for effective coformulation of the two agents. In an initial clinical trial, ALKS 33 at 10-mg and 20-mg oral doses completely blocked mu agonist effects of serial pulses of remifentanil in opioid-experienced volunteers. The effects were assessed by both physiologic measures such as pupilometry and subjective measures such as visual analogue scale assessment of drug liking and drug high.

"Hopefully (the findings) will ultimately enable broad utilization of opioid modulation in psychiatric disorders."

The duration of blockade was greater than 24 hours following a single dose, Dr. Ehrich said. Subsequently, a drug-drug interaction study was performed to identify the ALKS 33 and buprenorphine ratio that would provide complete blockade. The findings showed that when administered together with 8 mg of buprenorphine, ALKS 33 caused partial attenuation of mu effects at a 1-mg dose, and complete blockade of mu effects at doses of 4 mg or greater.

In addition, a double-blind, placebo-controlled pilot study showed rapid efficacy of ALKS 5461 in 32 patients with major depressive disorder who failed to respond adequately to treatment with selective serotonin reuptake inhibitors (SSRIs) or selective serotonin-norepinephrine reuptake inhibitors (SNRIs), he said.

Patients were randomized to receive daily sublingual treatment with ALKS 5461 at an 8:1 ratio of buprenorphine and ALKS 33, which provided partial blockade of buprenorphine mu agonist effects, or a 1:1 ratio, which provided complete blockade of the effects. Patients continued on their SSRI or SNRI treatments.

Based on outcomes using the Hamilton Depression Rating Scale (HAMD-17) and the Montgomery-Asberg Depression Rating Scale (MADRS), efficacy was seen with both dose ratios at 7 days.

"What was a little surprising to us was that we actually saw a greater reduction [in symptoms] with full vs. partial blockade," Dr. Ehrich said, adding that the patterns on MADRS scores were similar with both ratios, but "every patient on the full blockade ratio demonstrated a response."

Furthermore, treatment was well tolerated, he said. The most common adverse events were those typically seen with opioid treatment, including dizziness, nausea, vomiting, and sedation, which occurred more frequently with partial blockade.

These early findings suggest that the therapeutic effects of opioids in mood disorders can be decoupled from the mu agonist effects of drug high and euphoria, thereby "bringing the ‘opium cure’ into the 21st century in the context of the most pharmacologically rational and responsible way, and in the context of data from controlled clinical trials," Dr. Ehrich said.

Indeed, ALKS 5461 may represent a new rapid-onset treatment approach for depression and other psychiatric disorders, such as addictive disorder, he said.

A phase II study of the agent is underway in patients with major depressive disorder, and a cocaine-interaction study is also underway.

"Hopefully (the findings) will ultimately enable broad utilization of opioid modulation in psychiatric disorders," he said.

The ALKS 5461 studies were funded in part by the National Institute on Drug Abuse. Dr. Ehrich is employed by Alkermes, which is developing ALKS 5461.

PHOENIX – A sustained-release formulation of the investigational drug levomilnacipran was found superior to placebo for improving depressive symptoms in adults with major depressive disorder.

The randomized, double-blind phase III trial included more than 700 patients. Treatment also was associated with significant and clinically meaningful improvements in functional health and well-being, the investigators reported.

Patients were randomized to receive daily treatment at dosages of 40 mg, 80 mg, or 120 mg of levomilnacipran SR, a selective serotonin and norepinephrine reuptake inhibitor (SNRI). Improvement in depressive symptoms was dose proportional and statistically significant, compared with placebo, reported Carl Gommoll of Forest Research Institute and his colleagues in a poster at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

On the Montgomery-Asberg Depression Rating Scale–Clinician Rated (MADRS-CR), the least-squares mean difference (LSMD) versus placebo for total score change from baseline was –3.23 for the 40-mg group, –3.99 for the 80-mg group, and –4.86 for the 120-mg group (181, 181, and 183 patients, respectively), the investigators said.

The 80-mg and 120-mg groups also experienced significantly greater improvement, compared with placebo, on the Sheehan Disability Scale, the Hamilton Depression Rating Scale, and the Clinical Global Impressions–Severity and –Improvement assessments.

In a post hoc analysis, the superiority of levomilnacipran SR at the 80-mg and 120-mg doses was demonstrated across symptom domains, as evidenced by significantly greater decreases in most MADRS-CR single-item scores, the investigators reported.

In a separate analysis and poster presentation, Steven I. Blum, also of Forest Research Institute, and his colleagues reported that the patients treated with levomilnacipran SR experienced significantly greater improvement in Mental Component Summary scores on the SF-36v2 acute Health Survey, compared with those in the placebo group (LSMD of 4.4).

"A treatment advantage of three points in the mean treatment group difference is considered clinically relevant," the investigators explained, also noting that the treatment group patients experienced significant improvements, compared with the placebo group, on the individual SF-36 dimensions of general health, vitality, social functioning, role emotional, and mental health (LSMDs of 2.3, 2.4, 3.1, 3.1, and 4.3, respectively).

These differences also exceeded minimally important difference thresholds for the domain and are considered clinically relevant, they said.

Improvements with treatment vs. placebo also were seen on the Physical Component Summary and other individual dimensions of the SF-36 (specifically, physical functions, role physical, and bodily pain), but these did not reach statistical significance.

These findings suggest that treatment with levomilnacipran SR is associated with clinically meaningful, statistically significant improvements in functional health and well being, the investigators said.

Together, the findings of these two analyses of phase III trial data contribute to a recent series of positive findings with respect to levomilnacipran SR, which the investigators describe as a "potent and selective SNRI with 2-fold greater potency for norepinephrine relative to serotonin reuptake inhibition and over 10-fold greater selectivity for norepinephrine reuptake inhibition, compared with duloxetine and venlafaxine."

The sustained-release formulation was developed to allow once-daily dosing and was shown in a prior, flexible-dose (75-100 mg) randomized controlled trial to be superior to placebo on all efficacy measures.

Patients in the current double-blind, multicenter, parallel-group, fixed-dose study were adults aged 18-65 years who met the Diagnostic and Statistical Manual-IV-TR (text revision) criteria for major depressive disorder. All had a current major depressive episode of at least 8 weeks’ duration at study entry, as well as a score of 30 or more (mean of 36) on MADRS-CR.

Following a 1-week, single-blind placebo lead-in period, participants were randomized in a double-blind fashion to 8 weeks of active treatment or placebo. Those in the levomilnacipran SR treatment groups received an initial dose of 20 mg, titrated to the target dose over 7 days. The treatment phase was followed by a 2-week double-blind down-taper.

Treatment was generally well tolerated, although significantly more treatment-group patients (7.3%, 14.5%, and 6.7% for the 40-, 80-, and 120-mg groups) than placebo-group patients (1.7%) discontinued because of adverse events, the investigators noted.

The most common treatment-emergent adverse events were nausea, constipation, heart rate increase, and hyperhidrosis; most were mild or moderate in intensity.

The positive findings with respect to levomilnacipran SR reinforce its potential as an effective treatment option for adults with MDD, according to a statement from Forest Laboratories Inc., released earlier this year. The statement noted that the company anticipates filing a new drug application with the U.S. Food and Drug Administration in the third quarter of 2012.

This study was supported by Forest Laboratories and Pierre Fabre Medicament, the makers of levomilnacipran SR. Forest Research Institute, which employs both Dr. Blum and Dr. Gommoll, is the scientific division of Forest Laboratories.

PHOENIX – A sustained-release formulation of the investigational drug levomilnacipran was found superior to placebo for improving depressive symptoms in adults with major depressive disorder.

The randomized, double-blind phase III trial included more than 700 patients. Treatment also was associated with significant and clinically meaningful improvements in functional health and well-being, the investigators reported.

Patients were randomized to receive daily treatment at dosages of 40 mg, 80 mg, or 120 mg of levomilnacipran SR, a selective serotonin and norepinephrine reuptake inhibitor (SNRI). Improvement in depressive symptoms was dose proportional and statistically significant, compared with placebo, reported Carl Gommoll of Forest Research Institute and his colleagues in a poster at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

On the Montgomery-Asberg Depression Rating Scale–Clinician Rated (MADRS-CR), the least-squares mean difference (LSMD) versus placebo for total score change from baseline was –3.23 for the 40-mg group, –3.99 for the 80-mg group, and –4.86 for the 120-mg group (181, 181, and 183 patients, respectively), the investigators said.

The 80-mg and 120-mg groups also experienced significantly greater improvement, compared with placebo, on the Sheehan Disability Scale, the Hamilton Depression Rating Scale, and the Clinical Global Impressions–Severity and –Improvement assessments.

In a post hoc analysis, the superiority of levomilnacipran SR at the 80-mg and 120-mg doses was demonstrated across symptom domains, as evidenced by significantly greater decreases in most MADRS-CR single-item scores, the investigators reported.

In a separate analysis and poster presentation, Steven I. Blum, also of Forest Research Institute, and his colleagues reported that the patients treated with levomilnacipran SR experienced significantly greater improvement in Mental Component Summary scores on the SF-36v2 acute Health Survey, compared with those in the placebo group (LSMD of 4.4).

"A treatment advantage of three points in the mean treatment group difference is considered clinically relevant," the investigators explained, also noting that the treatment group patients experienced significant improvements, compared with the placebo group, on the individual SF-36 dimensions of general health, vitality, social functioning, role emotional, and mental health (LSMDs of 2.3, 2.4, 3.1, 3.1, and 4.3, respectively).

These differences also exceeded minimally important difference thresholds for the domain and are considered clinically relevant, they said.

Improvements with treatment vs. placebo also were seen on the Physical Component Summary and other individual dimensions of the SF-36 (specifically, physical functions, role physical, and bodily pain), but these did not reach statistical significance.

These findings suggest that treatment with levomilnacipran SR is associated with clinically meaningful, statistically significant improvements in functional health and well being, the investigators said.

Together, the findings of these two analyses of phase III trial data contribute to a recent series of positive findings with respect to levomilnacipran SR, which the investigators describe as a "potent and selective SNRI with 2-fold greater potency for norepinephrine relative to serotonin reuptake inhibition and over 10-fold greater selectivity for norepinephrine reuptake inhibition, compared with duloxetine and venlafaxine."

The sustained-release formulation was developed to allow once-daily dosing and was shown in a prior, flexible-dose (75-100 mg) randomized controlled trial to be superior to placebo on all efficacy measures.

Patients in the current double-blind, multicenter, parallel-group, fixed-dose study were adults aged 18-65 years who met the Diagnostic and Statistical Manual-IV-TR (text revision) criteria for major depressive disorder. All had a current major depressive episode of at least 8 weeks’ duration at study entry, as well as a score of 30 or more (mean of 36) on MADRS-CR.

Following a 1-week, single-blind placebo lead-in period, participants were randomized in a double-blind fashion to 8 weeks of active treatment or placebo. Those in the levomilnacipran SR treatment groups received an initial dose of 20 mg, titrated to the target dose over 7 days. The treatment phase was followed by a 2-week double-blind down-taper.

Treatment was generally well tolerated, although significantly more treatment-group patients (7.3%, 14.5%, and 6.7% for the 40-, 80-, and 120-mg groups) than placebo-group patients (1.7%) discontinued because of adverse events, the investigators noted.

The most common treatment-emergent adverse events were nausea, constipation, heart rate increase, and hyperhidrosis; most were mild or moderate in intensity.

The positive findings with respect to levomilnacipran SR reinforce its potential as an effective treatment option for adults with MDD, according to a statement from Forest Laboratories Inc., released earlier this year. The statement noted that the company anticipates filing a new drug application with the U.S. Food and Drug Administration in the third quarter of 2012.

This study was supported by Forest Laboratories and Pierre Fabre Medicament, the makers of levomilnacipran SR. Forest Research Institute, which employs both Dr. Blum and Dr. Gommoll, is the scientific division of Forest Laboratories.

PHOENIX – A sustained-release formulation of the investigational drug levomilnacipran was found superior to placebo for improving depressive symptoms in adults with major depressive disorder.

The randomized, double-blind phase III trial included more than 700 patients. Treatment also was associated with significant and clinically meaningful improvements in functional health and well-being, the investigators reported.

Patients were randomized to receive daily treatment at dosages of 40 mg, 80 mg, or 120 mg of levomilnacipran SR, a selective serotonin and norepinephrine reuptake inhibitor (SNRI). Improvement in depressive symptoms was dose proportional and statistically significant, compared with placebo, reported Carl Gommoll of Forest Research Institute and his colleagues in a poster at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

On the Montgomery-Asberg Depression Rating Scale–Clinician Rated (MADRS-CR), the least-squares mean difference (LSMD) versus placebo for total score change from baseline was –3.23 for the 40-mg group, –3.99 for the 80-mg group, and –4.86 for the 120-mg group (181, 181, and 183 patients, respectively), the investigators said.

The 80-mg and 120-mg groups also experienced significantly greater improvement, compared with placebo, on the Sheehan Disability Scale, the Hamilton Depression Rating Scale, and the Clinical Global Impressions–Severity and –Improvement assessments.

In a post hoc analysis, the superiority of levomilnacipran SR at the 80-mg and 120-mg doses was demonstrated across symptom domains, as evidenced by significantly greater decreases in most MADRS-CR single-item scores, the investigators reported.

In a separate analysis and poster presentation, Steven I. Blum, also of Forest Research Institute, and his colleagues reported that the patients treated with levomilnacipran SR experienced significantly greater improvement in Mental Component Summary scores on the SF-36v2 acute Health Survey, compared with those in the placebo group (LSMD of 4.4).

"A treatment advantage of three points in the mean treatment group difference is considered clinically relevant," the investigators explained, also noting that the treatment group patients experienced significant improvements, compared with the placebo group, on the individual SF-36 dimensions of general health, vitality, social functioning, role emotional, and mental health (LSMDs of 2.3, 2.4, 3.1, 3.1, and 4.3, respectively).

These differences also exceeded minimally important difference thresholds for the domain and are considered clinically relevant, they said.

Improvements with treatment vs. placebo also were seen on the Physical Component Summary and other individual dimensions of the SF-36 (specifically, physical functions, role physical, and bodily pain), but these did not reach statistical significance.

These findings suggest that treatment with levomilnacipran SR is associated with clinically meaningful, statistically significant improvements in functional health and well being, the investigators said.

Together, the findings of these two analyses of phase III trial data contribute to a recent series of positive findings with respect to levomilnacipran SR, which the investigators describe as a "potent and selective SNRI with 2-fold greater potency for norepinephrine relative to serotonin reuptake inhibition and over 10-fold greater selectivity for norepinephrine reuptake inhibition, compared with duloxetine and venlafaxine."

The sustained-release formulation was developed to allow once-daily dosing and was shown in a prior, flexible-dose (75-100 mg) randomized controlled trial to be superior to placebo on all efficacy measures.

Patients in the current double-blind, multicenter, parallel-group, fixed-dose study were adults aged 18-65 years who met the Diagnostic and Statistical Manual-IV-TR (text revision) criteria for major depressive disorder. All had a current major depressive episode of at least 8 weeks’ duration at study entry, as well as a score of 30 or more (mean of 36) on MADRS-CR.

Following a 1-week, single-blind placebo lead-in period, participants were randomized in a double-blind fashion to 8 weeks of active treatment or placebo. Those in the levomilnacipran SR treatment groups received an initial dose of 20 mg, titrated to the target dose over 7 days. The treatment phase was followed by a 2-week double-blind down-taper.

Treatment was generally well tolerated, although significantly more treatment-group patients (7.3%, 14.5%, and 6.7% for the 40-, 80-, and 120-mg groups) than placebo-group patients (1.7%) discontinued because of adverse events, the investigators noted.

The most common treatment-emergent adverse events were nausea, constipation, heart rate increase, and hyperhidrosis; most were mild or moderate in intensity.

The positive findings with respect to levomilnacipran SR reinforce its potential as an effective treatment option for adults with MDD, according to a statement from Forest Laboratories Inc., released earlier this year. The statement noted that the company anticipates filing a new drug application with the U.S. Food and Drug Administration in the third quarter of 2012.

This study was supported by Forest Laboratories and Pierre Fabre Medicament, the makers of levomilnacipran SR. Forest Research Institute, which employs both Dr. Blum and Dr. Gommoll, is the scientific division of Forest Laboratories.

PHOENIX – Vilazodone appears to be effective in patients with depression across severity subgroups and isn’t associated with meaningful weight gains, based on post hoc analyses of data from phase III studies.

The findings were based on data from 869 patients who were part of the two trials that examined the drug’s safety; 31% had moderate depression based on scores of less than 30 on the Montgomery-Asberg Depression Rating Scale, 49% had moderately severe depression (MADRS of 30-35), and 20% had severe depression (MADRS of 35 or greater). Patients on vilazodone had improvements that exceeded those of patients on placebo. The least squares mean differences for change were –2.9 (moderate depression), –2.3 (moderately severe depression), and –4.1 (severe depression), reported Dr. Donald S. Robinson of Worldwide Drug Development, Shelburne, Vt., and his colleagues in a poster presented at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Differences exceeded 2.0 in all three subgroups, representing clinically significant effects, according to the researchers.

In the treatment and placebo groups, the respective percent responses were 41% and 31% in those with moderate depression, 41% and 29% in those with moderately severe depression, and 44% and 26% those with severe depression. The adverse events profiles were similar for vilazodone and placebo across the severity groups.

In another poster, Dr. John Edwards of Forest Research Institute, Jersey City, N.J., and his colleagues reported an analysis of vilazodone effectiveness. He found that the number needed to treat (NNT) was 12 to achieve a MADRS of 10 or less and 8 for a MADRS of 12 or less. The number needed to harm was 26 to result in a discontinuation caused by adverse events.

A MADRS of 10 or less is generally considered to be evidence of clinical relevance in depression treatment, and the NNT for response in this analysis – using both MADRS and the Clinical Global Impression of Improvement (CGI-I) criteria – was "sufficient to regard improvement by vilazodone as clinically significant," the investigators said, noting also that the NNT values for remission were "well within the range of those observed for other antidepressants in clinical studies."

The analysis suggested a lower risk of discontinuation due to adverse events relative to clinically meaningful improvement for vilazodone, they concluded.

A third post hoc analysis of the pooled phase III trial data and the 52-week open-label trial indicated that vilazodone had little effect on body weight and clinical laboratory measures.

The mean baseline body weight of patients in the treatment and placebo groups was 86.0 kg and 86.5 kg, respectively, and the mean weight of treated patients in the open-label study was 89.6 kg. Mean baseline body mass index was 30.2 kg/m², 30.1 kg/m², and 31.6 kg/m² in those groups, respectively. The mean change in body weight from baseline to the end of treatment for vilazodone and placebo patients was 0.16 kg and 0.18 kg, respectively, overall, reported Dr. Michael E. Thase of the University of Pennsylvania, Philadelphia, and his colleagues in a poster.

There also was little difference between the treatment and placebo groups after stratification based on normal weight, overweight, and obese status, (mean change of 0.0 kg and 0.32 kg, respectively, for normal weight patients; 0.08 kg and 0.57 kg for overweight patients; and –0.39 kg and 0.18 kg for obese patients).

In the open-label study patients, the mean change in body weight from baseline to the end of treatment was 1.20 kg overall, and 1.13, 1.21, 1.50, and 1.06 kg for underweight, normal weight, overweight, and obese patients, respectively, they said. Clinically significant weight gain occurred in one patient each in the treatment and placebo groups in the phase III trials, and in 2%, 3%, and 5% of the normal, overweight, and obese patients, respectively, in the open-label trial population.

Additionally, no significant differences between the treatment and placebo groups with respect to changes in liver enzymes and blood glucose were seen in the phase III trials, the investigators said.

The studies were supported by funding from Forest Laboratories. Dr. Robinson and Dr. Thase reported receiving grant support and/or consulting fees from Forest Research Institute, a scientific division of Forest Labs. Dr. Robinson and several other study authors are employees of Forest Research Institute.

PHOENIX – Vilazodone appears to be effective in patients with depression across severity subgroups and isn’t associated with meaningful weight gains, based on post hoc analyses of data from phase III studies.

The findings were based on data from 869 patients who were part of the two trials that examined the drug’s safety; 31% had moderate depression based on scores of less than 30 on the Montgomery-Asberg Depression Rating Scale, 49% had moderately severe depression (MADRS of 30-35), and 20% had severe depression (MADRS of 35 or greater). Patients on vilazodone had improvements that exceeded those of patients on placebo. The least squares mean differences for change were –2.9 (moderate depression), –2.3 (moderately severe depression), and –4.1 (severe depression), reported Dr. Donald S. Robinson of Worldwide Drug Development, Shelburne, Vt., and his colleagues in a poster presented at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Differences exceeded 2.0 in all three subgroups, representing clinically significant effects, according to the researchers.

In the treatment and placebo groups, the respective percent responses were 41% and 31% in those with moderate depression, 41% and 29% in those with moderately severe depression, and 44% and 26% those with severe depression. The adverse events profiles were similar for vilazodone and placebo across the severity groups.

In another poster, Dr. John Edwards of Forest Research Institute, Jersey City, N.J., and his colleagues reported an analysis of vilazodone effectiveness. He found that the number needed to treat (NNT) was 12 to achieve a MADRS of 10 or less and 8 for a MADRS of 12 or less. The number needed to harm was 26 to result in a discontinuation caused by adverse events.

A MADRS of 10 or less is generally considered to be evidence of clinical relevance in depression treatment, and the NNT for response in this analysis – using both MADRS and the Clinical Global Impression of Improvement (CGI-I) criteria – was "sufficient to regard improvement by vilazodone as clinically significant," the investigators said, noting also that the NNT values for remission were "well within the range of those observed for other antidepressants in clinical studies."

The analysis suggested a lower risk of discontinuation due to adverse events relative to clinically meaningful improvement for vilazodone, they concluded.

A third post hoc analysis of the pooled phase III trial data and the 52-week open-label trial indicated that vilazodone had little effect on body weight and clinical laboratory measures.

The mean baseline body weight of patients in the treatment and placebo groups was 86.0 kg and 86.5 kg, respectively, and the mean weight of treated patients in the open-label study was 89.6 kg. Mean baseline body mass index was 30.2 kg/m², 30.1 kg/m², and 31.6 kg/m² in those groups, respectively. The mean change in body weight from baseline to the end of treatment for vilazodone and placebo patients was 0.16 kg and 0.18 kg, respectively, overall, reported Dr. Michael E. Thase of the University of Pennsylvania, Philadelphia, and his colleagues in a poster.

There also was little difference between the treatment and placebo groups after stratification based on normal weight, overweight, and obese status, (mean change of 0.0 kg and 0.32 kg, respectively, for normal weight patients; 0.08 kg and 0.57 kg for overweight patients; and –0.39 kg and 0.18 kg for obese patients).

In the open-label study patients, the mean change in body weight from baseline to the end of treatment was 1.20 kg overall, and 1.13, 1.21, 1.50, and 1.06 kg for underweight, normal weight, overweight, and obese patients, respectively, they said. Clinically significant weight gain occurred in one patient each in the treatment and placebo groups in the phase III trials, and in 2%, 3%, and 5% of the normal, overweight, and obese patients, respectively, in the open-label trial population.

Additionally, no significant differences between the treatment and placebo groups with respect to changes in liver enzymes and blood glucose were seen in the phase III trials, the investigators said.

The studies were supported by funding from Forest Laboratories. Dr. Robinson and Dr. Thase reported receiving grant support and/or consulting fees from Forest Research Institute, a scientific division of Forest Labs. Dr. Robinson and several other study authors are employees of Forest Research Institute.

PHOENIX – Vilazodone appears to be effective in patients with depression across severity subgroups and isn’t associated with meaningful weight gains, based on post hoc analyses of data from phase III studies.

The findings were based on data from 869 patients who were part of the two trials that examined the drug’s safety; 31% had moderate depression based on scores of less than 30 on the Montgomery-Asberg Depression Rating Scale, 49% had moderately severe depression (MADRS of 30-35), and 20% had severe depression (MADRS of 35 or greater). Patients on vilazodone had improvements that exceeded those of patients on placebo. The least squares mean differences for change were –2.9 (moderate depression), –2.3 (moderately severe depression), and –4.1 (severe depression), reported Dr. Donald S. Robinson of Worldwide Drug Development, Shelburne, Vt., and his colleagues in a poster presented at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Differences exceeded 2.0 in all three subgroups, representing clinically significant effects, according to the researchers.

In the treatment and placebo groups, the respective percent responses were 41% and 31% in those with moderate depression, 41% and 29% in those with moderately severe depression, and 44% and 26% those with severe depression. The adverse events profiles were similar for vilazodone and placebo across the severity groups.

In another poster, Dr. John Edwards of Forest Research Institute, Jersey City, N.J., and his colleagues reported an analysis of vilazodone effectiveness. He found that the number needed to treat (NNT) was 12 to achieve a MADRS of 10 or less and 8 for a MADRS of 12 or less. The number needed to harm was 26 to result in a discontinuation caused by adverse events.

A MADRS of 10 or less is generally considered to be evidence of clinical relevance in depression treatment, and the NNT for response in this analysis – using both MADRS and the Clinical Global Impression of Improvement (CGI-I) criteria – was "sufficient to regard improvement by vilazodone as clinically significant," the investigators said, noting also that the NNT values for remission were "well within the range of those observed for other antidepressants in clinical studies."

The analysis suggested a lower risk of discontinuation due to adverse events relative to clinically meaningful improvement for vilazodone, they concluded.

A third post hoc analysis of the pooled phase III trial data and the 52-week open-label trial indicated that vilazodone had little effect on body weight and clinical laboratory measures.

The mean baseline body weight of patients in the treatment and placebo groups was 86.0 kg and 86.5 kg, respectively, and the mean weight of treated patients in the open-label study was 89.6 kg. Mean baseline body mass index was 30.2 kg/m², 30.1 kg/m², and 31.6 kg/m² in those groups, respectively. The mean change in body weight from baseline to the end of treatment for vilazodone and placebo patients was 0.16 kg and 0.18 kg, respectively, overall, reported Dr. Michael E. Thase of the University of Pennsylvania, Philadelphia, and his colleagues in a poster.

There also was little difference between the treatment and placebo groups after stratification based on normal weight, overweight, and obese status, (mean change of 0.0 kg and 0.32 kg, respectively, for normal weight patients; 0.08 kg and 0.57 kg for overweight patients; and –0.39 kg and 0.18 kg for obese patients).

In the open-label study patients, the mean change in body weight from baseline to the end of treatment was 1.20 kg overall, and 1.13, 1.21, 1.50, and 1.06 kg for underweight, normal weight, overweight, and obese patients, respectively, they said. Clinically significant weight gain occurred in one patient each in the treatment and placebo groups in the phase III trials, and in 2%, 3%, and 5% of the normal, overweight, and obese patients, respectively, in the open-label trial population.

Additionally, no significant differences between the treatment and placebo groups with respect to changes in liver enzymes and blood glucose were seen in the phase III trials, the investigators said.

The studies were supported by funding from Forest Laboratories. Dr. Robinson and Dr. Thase reported receiving grant support and/or consulting fees from Forest Research Institute, a scientific division of Forest Labs. Dr. Robinson and several other study authors are employees of Forest Research Institute.

PHOENIX – Vilazodone was associated with significantly higher rates of response and remission than placebo, and it demonstrated efficacy across all symptoms in patients with major depressive disorder in an analysis of pooled data from two pivotal randomized controlled trials.

The efficacy of the serotonin reuptake inhibitor and 5-HT receptor partial agonist was established in the two 8-week phase III studies, and safety and tolerability were demonstrated in a 52-week open-label phase III study. These findings led to the 2011 Food and Drug Administration approval of vilazodone hydrochloride under the trade name of Viibryd for treatment of MDD in adults.

The current post hoc pooled analysis of data from the two 8-week studies further demonstrates the drug’s efficacy across the symptoms of depression, Dr. Arif Khan and colleagues reported in a poster at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Compared with 432 patients who received placebo, the 431 patients randomized to receive vilazodone experienced significant improvements in Montgomery-Åsberg Depression Rating Scale (MADRS) scores (least squared mean difference of –2.79), as well as significant improvement on all secondary measures, including the Hamilton Depression Rating Scale (HAMD), the Clinical Global Impressions-Improvement (CGI-I) and Severity (CGI-S) scales, and the Hamilton Anxiety Rating Scale (HAMA), according to Dr. Khan of the Northwest Clinical Research Center in Bellevue, Wash.

Response defined by at least 50% improvement on the MADRS occurred in 42% of vilazodone and 29% of placebo patients. Response defined by a 50% or greater improvement on the HAMD occurred in 44% and 33% of the patients, respectively, and response defined by achievement of a CGI-I score of 2 or less occurred in 49% and 35% of the patients, respectively. Remission defined as a MADRS score of 10 or less occurred in 29% of the vilazodone and 20% of the placebo patients, and remission defined as a MADRS score of 12 or less occurred in 35% vs. 22% of the patients, respectively.

Significant improvement in favor of vilazodone also was seen on change from baseline in every MADRS single item, including apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts.

The patients were adults aged 18-65 years in the first trial and 18-70 years in the second. All met diagnostic criteria for MDD according to the DSM-IV-TR, and they all underwent a washout period of at least 2 weeks, a 1-week screening period, and an 8-week double-blind treatment period. Vilazodone was titrated from a 10-mg dose once daily for 7 days to 20 mg once daily for the next 7 days and 40 mg once daily thereafter.

The findings demonstrate that vilazodone is significantly superior to placebo on all depression rating scales tested, Dr. Khan noted.

"Additionally, superiority versus placebo on all MADRS single items demonstrated the broad efficacy of vilazodone across the spectrum of depression symptoms," he wrote, also noting that "the selection of a therapeutic agent that effectively resolves a broad spectrum of symptoms and promotes a return to full functioning is an important component of depression treatment."

Dr. Khan reported having no conflicts of interest to disclose. This study was supported by Forest Laboratories. Other authors are employees of Forest Research Institute, a scientific subsidiary of Forest Laboratories.

PHOENIX – Vilazodone was associated with significantly higher rates of response and remission than placebo, and it demonstrated efficacy across all symptoms in patients with major depressive disorder in an analysis of pooled data from two pivotal randomized controlled trials.

The efficacy of the serotonin reuptake inhibitor and 5-HT receptor partial agonist was established in the two 8-week phase III studies, and safety and tolerability were demonstrated in a 52-week open-label phase III study. These findings led to the 2011 Food and Drug Administration approval of vilazodone hydrochloride under the trade name of Viibryd for treatment of MDD in adults.

The current post hoc pooled analysis of data from the two 8-week studies further demonstrates the drug’s efficacy across the symptoms of depression, Dr. Arif Khan and colleagues reported in a poster at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Compared with 432 patients who received placebo, the 431 patients randomized to receive vilazodone experienced significant improvements in Montgomery-Åsberg Depression Rating Scale (MADRS) scores (least squared mean difference of –2.79), as well as significant improvement on all secondary measures, including the Hamilton Depression Rating Scale (HAMD), the Clinical Global Impressions-Improvement (CGI-I) and Severity (CGI-S) scales, and the Hamilton Anxiety Rating Scale (HAMA), according to Dr. Khan of the Northwest Clinical Research Center in Bellevue, Wash.

Response defined by at least 50% improvement on the MADRS occurred in 42% of vilazodone and 29% of placebo patients. Response defined by a 50% or greater improvement on the HAMD occurred in 44% and 33% of the patients, respectively, and response defined by achievement of a CGI-I score of 2 or less occurred in 49% and 35% of the patients, respectively. Remission defined as a MADRS score of 10 or less occurred in 29% of the vilazodone and 20% of the placebo patients, and remission defined as a MADRS score of 12 or less occurred in 35% vs. 22% of the patients, respectively.

Significant improvement in favor of vilazodone also was seen on change from baseline in every MADRS single item, including apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts.

The patients were adults aged 18-65 years in the first trial and 18-70 years in the second. All met diagnostic criteria for MDD according to the DSM-IV-TR, and they all underwent a washout period of at least 2 weeks, a 1-week screening period, and an 8-week double-blind treatment period. Vilazodone was titrated from a 10-mg dose once daily for 7 days to 20 mg once daily for the next 7 days and 40 mg once daily thereafter.

The findings demonstrate that vilazodone is significantly superior to placebo on all depression rating scales tested, Dr. Khan noted.

"Additionally, superiority versus placebo on all MADRS single items demonstrated the broad efficacy of vilazodone across the spectrum of depression symptoms," he wrote, also noting that "the selection of a therapeutic agent that effectively resolves a broad spectrum of symptoms and promotes a return to full functioning is an important component of depression treatment."

Dr. Khan reported having no conflicts of interest to disclose. This study was supported by Forest Laboratories. Other authors are employees of Forest Research Institute, a scientific subsidiary of Forest Laboratories.

PHOENIX – Vilazodone was associated with significantly higher rates of response and remission than placebo, and it demonstrated efficacy across all symptoms in patients with major depressive disorder in an analysis of pooled data from two pivotal randomized controlled trials.

The efficacy of the serotonin reuptake inhibitor and 5-HT receptor partial agonist was established in the two 8-week phase III studies, and safety and tolerability were demonstrated in a 52-week open-label phase III study. These findings led to the 2011 Food and Drug Administration approval of vilazodone hydrochloride under the trade name of Viibryd for treatment of MDD in adults.

The current post hoc pooled analysis of data from the two 8-week studies further demonstrates the drug’s efficacy across the symptoms of depression, Dr. Arif Khan and colleagues reported in a poster at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Compared with 432 patients who received placebo, the 431 patients randomized to receive vilazodone experienced significant improvements in Montgomery-Åsberg Depression Rating Scale (MADRS) scores (least squared mean difference of –2.79), as well as significant improvement on all secondary measures, including the Hamilton Depression Rating Scale (HAMD), the Clinical Global Impressions-Improvement (CGI-I) and Severity (CGI-S) scales, and the Hamilton Anxiety Rating Scale (HAMA), according to Dr. Khan of the Northwest Clinical Research Center in Bellevue, Wash.

Response defined by at least 50% improvement on the MADRS occurred in 42% of vilazodone and 29% of placebo patients. Response defined by a 50% or greater improvement on the HAMD occurred in 44% and 33% of the patients, respectively, and response defined by achievement of a CGI-I score of 2 or less occurred in 49% and 35% of the patients, respectively. Remission defined as a MADRS score of 10 or less occurred in 29% of the vilazodone and 20% of the placebo patients, and remission defined as a MADRS score of 12 or less occurred in 35% vs. 22% of the patients, respectively.

Significant improvement in favor of vilazodone also was seen on change from baseline in every MADRS single item, including apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts.

The patients were adults aged 18-65 years in the first trial and 18-70 years in the second. All met diagnostic criteria for MDD according to the DSM-IV-TR, and they all underwent a washout period of at least 2 weeks, a 1-week screening period, and an 8-week double-blind treatment period. Vilazodone was titrated from a 10-mg dose once daily for 7 days to 20 mg once daily for the next 7 days and 40 mg once daily thereafter.

The findings demonstrate that vilazodone is significantly superior to placebo on all depression rating scales tested, Dr. Khan noted.

"Additionally, superiority versus placebo on all MADRS single items demonstrated the broad efficacy of vilazodone across the spectrum of depression symptoms," he wrote, also noting that "the selection of a therapeutic agent that effectively resolves a broad spectrum of symptoms and promotes a return to full functioning is an important component of depression treatment."

Dr. Khan reported having no conflicts of interest to disclose. This study was supported by Forest Laboratories. Other authors are employees of Forest Research Institute, a scientific subsidiary of Forest Laboratories.

PHOENIX – The novel atypical antipsychotic drug cariprazine is effective for the treatment of acute mania associated with bipolar I disorder, according to findings from a randomized, placebo-controlled phase III study.

In 158 patients randomized to receive 3 weeks of double-blind treatment with the orally active dopamine D3-preferring D3/D2 receptor partial agonist, the mean improvement on the Young Mania Rating Scale (YMRS), based on a mixed-effects model of repeated measures, was significantly greater than the mean improvement in 151 patients randomized to receive placebo, Anjana Bose, Ph.D. and her colleagues reported in a poster at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Cariprazine demonstrated fast onset of action, with a statistically greater improvement vs. placebo seen by day 4 of treatment and at every visit thereafter.

Significantly more patients in the active treatment group met the YMRS criteria for response (59% vs. 44% taking placebo achieved at least a 50% score reduction from baseline) and remission (52% vs. 35% achieved a total score of 12 or less) at 3 weeks, she said.

The mean improvement on the Clinical Global Impressions-Severity scale also was significantly greater in the treatment group at week 3, as was the reduction in Positive and Negative Syndrome Scale (PANSS) score, according to Dr. Bose of Forest Research Institute, Jersey City, N.J.

Of note, cariprazine demonstrated fast onset of action, with a statistically greater improvement vs. placebo seen by day 4 of treatment and at every visit thereafter, she said.

Patients in the 6-week multicenter study were adults aged 18-65 years with acute mania associated with bipolar I disorder (as defined by the DSM-IV-TR) and a YMRS score of 20 or higher. The mean YMRS scores at baseline were similar at 32.3 (treatment group) and 32.1 (placebo).

Patients were hospitalized for a 4- to 7-day wash-out period and for at least the first 14 days of the 3-week treatment period. Those randomized to the treatment group received between 3 and 12 mg of cariprazine daily during those 3 weeks; treatment was initiated at a dose of 1.5 mg/day and increased in increments of 3 mg to a maximum of 12 mg/day by day 7, based on patient response and tolerability. The mean dose given was 7.5 mg/day.

Treatment was followed by a 2-week safety follow-up period.

A similar proportion of patients in the treatment and placebo groups (69% and 68%, respectively) completed the study; 10% of treatment-group patients and 7% of placebo-group patients discontinued treatment because of adverse effects. Treatment-emergent adverse events occurred in 80% and 63% of the patients in each group, respectively, and included worsening of mania in two treatment-group patients and five placebo-group patients and akathisia in five treatment-group patients.

The most common adverse events were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Extrapyramidal symptom–related adverse events occurred in 46% of the treatment and 12% of the placebo-group patients, Dr. Bose reported.

"Cariprazine is an orally active atypical antipsychotic candidate in clinical development for the treatment of schizophrenia and bipolar disorder. It has been hypothesized that a compound that exhibits high potency for both D3 and D2 receptors may have treatment advantages compared with currently available atypical antipsychotics," she wrote.

In this study, treatment was associated with a higher incidence of akathisia and extrapyramidal symptoms, but it was not associated with a mean increase in weight or metabolic parameters or with prolactin increase or QTc prolongation, she noted.

The drug was safe and generally well tolerated. The findings of this phase III study support those from an earlier phase II study in which cariprazine also was shown to be safe, well tolerated, and significantly superior to placebo for improvement of acute manic or mixed episodes, she concluded.

Dr. Bose is an employee of Forest Research Institute, a scientific subsidiary of Forest Laboratories, the maker of cariprazine and the sponsor of this study.

PHOENIX – The novel atypical antipsychotic drug cariprazine is effective for the treatment of acute mania associated with bipolar I disorder, according to findings from a randomized, placebo-controlled phase III study.

In 158 patients randomized to receive 3 weeks of double-blind treatment with the orally active dopamine D3-preferring D3/D2 receptor partial agonist, the mean improvement on the Young Mania Rating Scale (YMRS), based on a mixed-effects model of repeated measures, was significantly greater than the mean improvement in 151 patients randomized to receive placebo, Anjana Bose, Ph.D. and her colleagues reported in a poster at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Cariprazine demonstrated fast onset of action, with a statistically greater improvement vs. placebo seen by day 4 of treatment and at every visit thereafter.

Significantly more patients in the active treatment group met the YMRS criteria for response (59% vs. 44% taking placebo achieved at least a 50% score reduction from baseline) and remission (52% vs. 35% achieved a total score of 12 or less) at 3 weeks, she said.

The mean improvement on the Clinical Global Impressions-Severity scale also was significantly greater in the treatment group at week 3, as was the reduction in Positive and Negative Syndrome Scale (PANSS) score, according to Dr. Bose of Forest Research Institute, Jersey City, N.J.

Of note, cariprazine demonstrated fast onset of action, with a statistically greater improvement vs. placebo seen by day 4 of treatment and at every visit thereafter, she said.

Patients in the 6-week multicenter study were adults aged 18-65 years with acute mania associated with bipolar I disorder (as defined by the DSM-IV-TR) and a YMRS score of 20 or higher. The mean YMRS scores at baseline were similar at 32.3 (treatment group) and 32.1 (placebo).

Patients were hospitalized for a 4- to 7-day wash-out period and for at least the first 14 days of the 3-week treatment period. Those randomized to the treatment group received between 3 and 12 mg of cariprazine daily during those 3 weeks; treatment was initiated at a dose of 1.5 mg/day and increased in increments of 3 mg to a maximum of 12 mg/day by day 7, based on patient response and tolerability. The mean dose given was 7.5 mg/day.

Treatment was followed by a 2-week safety follow-up period.

A similar proportion of patients in the treatment and placebo groups (69% and 68%, respectively) completed the study; 10% of treatment-group patients and 7% of placebo-group patients discontinued treatment because of adverse effects. Treatment-emergent adverse events occurred in 80% and 63% of the patients in each group, respectively, and included worsening of mania in two treatment-group patients and five placebo-group patients and akathisia in five treatment-group patients.

The most common adverse events were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Extrapyramidal symptom–related adverse events occurred in 46% of the treatment and 12% of the placebo-group patients, Dr. Bose reported.

"Cariprazine is an orally active atypical antipsychotic candidate in clinical development for the treatment of schizophrenia and bipolar disorder. It has been hypothesized that a compound that exhibits high potency for both D3 and D2 receptors may have treatment advantages compared with currently available atypical antipsychotics," she wrote.

In this study, treatment was associated with a higher incidence of akathisia and extrapyramidal symptoms, but it was not associated with a mean increase in weight or metabolic parameters or with prolactin increase or QTc prolongation, she noted.

The drug was safe and generally well tolerated. The findings of this phase III study support those from an earlier phase II study in which cariprazine also was shown to be safe, well tolerated, and significantly superior to placebo for improvement of acute manic or mixed episodes, she concluded.

Dr. Bose is an employee of Forest Research Institute, a scientific subsidiary of Forest Laboratories, the maker of cariprazine and the sponsor of this study.

PHOENIX – The novel atypical antipsychotic drug cariprazine is effective for the treatment of acute mania associated with bipolar I disorder, according to findings from a randomized, placebo-controlled phase III study.

In 158 patients randomized to receive 3 weeks of double-blind treatment with the orally active dopamine D3-preferring D3/D2 receptor partial agonist, the mean improvement on the Young Mania Rating Scale (YMRS), based on a mixed-effects model of repeated measures, was significantly greater than the mean improvement in 151 patients randomized to receive placebo, Anjana Bose, Ph.D. and her colleagues reported in a poster at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Cariprazine demonstrated fast onset of action, with a statistically greater improvement vs. placebo seen by day 4 of treatment and at every visit thereafter.

Significantly more patients in the active treatment group met the YMRS criteria for response (59% vs. 44% taking placebo achieved at least a 50% score reduction from baseline) and remission (52% vs. 35% achieved a total score of 12 or less) at 3 weeks, she said.

The mean improvement on the Clinical Global Impressions-Severity scale also was significantly greater in the treatment group at week 3, as was the reduction in Positive and Negative Syndrome Scale (PANSS) score, according to Dr. Bose of Forest Research Institute, Jersey City, N.J.

Of note, cariprazine demonstrated fast onset of action, with a statistically greater improvement vs. placebo seen by day 4 of treatment and at every visit thereafter, she said.

Patients in the 6-week multicenter study were adults aged 18-65 years with acute mania associated with bipolar I disorder (as defined by the DSM-IV-TR) and a YMRS score of 20 or higher. The mean YMRS scores at baseline were similar at 32.3 (treatment group) and 32.1 (placebo).

Patients were hospitalized for a 4- to 7-day wash-out period and for at least the first 14 days of the 3-week treatment period. Those randomized to the treatment group received between 3 and 12 mg of cariprazine daily during those 3 weeks; treatment was initiated at a dose of 1.5 mg/day and increased in increments of 3 mg to a maximum of 12 mg/day by day 7, based on patient response and tolerability. The mean dose given was 7.5 mg/day.

Treatment was followed by a 2-week safety follow-up period.

A similar proportion of patients in the treatment and placebo groups (69% and 68%, respectively) completed the study; 10% of treatment-group patients and 7% of placebo-group patients discontinued treatment because of adverse effects. Treatment-emergent adverse events occurred in 80% and 63% of the patients in each group, respectively, and included worsening of mania in two treatment-group patients and five placebo-group patients and akathisia in five treatment-group patients.

The most common adverse events were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Extrapyramidal symptom–related adverse events occurred in 46% of the treatment and 12% of the placebo-group patients, Dr. Bose reported.

"Cariprazine is an orally active atypical antipsychotic candidate in clinical development for the treatment of schizophrenia and bipolar disorder. It has been hypothesized that a compound that exhibits high potency for both D3 and D2 receptors may have treatment advantages compared with currently available atypical antipsychotics," she wrote.

In this study, treatment was associated with a higher incidence of akathisia and extrapyramidal symptoms, but it was not associated with a mean increase in weight or metabolic parameters or with prolactin increase or QTc prolongation, she noted.

The drug was safe and generally well tolerated. The findings of this phase III study support those from an earlier phase II study in which cariprazine also was shown to be safe, well tolerated, and significantly superior to placebo for improvement of acute manic or mixed episodes, she concluded.

Dr. Bose is an employee of Forest Research Institute, a scientific subsidiary of Forest Laboratories, the maker of cariprazine and the sponsor of this study.